Therapeutic compounds and compositions

ABSTRACT

Compounds and compositions comprising compounds that modulate pyruvate kinase M2 (PKM2) are described herein. Also described herein are methods of using the compounds that modulate PKM2 in the treatment of cancer.

CLAIM OF PRIORITY

This application is a divisional of U.S. Ser. No. 16/243,247, filed Jan.9, 2019, which is a divisional of U.S. Ser. No. 16/010,717, filed Jun.18, 2018, which is a continuation of U.S. Ser. No. 15/412,976, filedJan. 23, 2017, now U.S. Pat. No. 10,029,987, which is a divisional ofU.S. Ser. No. 14/286,088, filed May 23, 2014, which is a divisional ofU.S. Ser. No. 12/826,630, filed Jun. 29, 2010, now U.S. Pat. No.8,785,450, issued Jul. 22, 2014, which claims priority from U.S. Ser.No. 61/221,430, filed Jun. 29, 2009 and U.S. Ser. No. 61/292,360, filedJan. 5, 2010, each of which is incorporated herein by reference in itsentirety.

BACKGROUND OF INVENTION

Cancer cells rely primarily on glycolysis to generate cellular energyand biochemical intermediates for biosynthesis of lipids andnucleotides, while the majority of “normal” cells in adult tissuesutilize aerobic respiration. This fundamental difference in cellularmetabolism between cancer cells and normal cells, termed the WarburgEffect, has been exploited for diagnostic purposes, but has not yet beenexploited for therapeutic benefit.

Pyruvate kinase (PK) is a metabolic enzyme that convertsphosphoenolpyruvate to pyruvate during glycolysis. Four PK isoformsexist in mammals: the L and R isoforms are expressed in liver and redblood cells, the M1 isoform is expressed in most adult tissues, and theM2 isoform is a splice variant of M1 expressed during embryonicdevelopment. All tumor cells exclusively express the embryonic M2isoform. A well-known difference between the M1 and M2 isoforms of PK isthat M2 is a low-activity enzyme that relies on allosteric activation bythe upstream glycolytic intermediate, fructose-1,6-bisphosphate (FBP),whereas M1 is a constitutively active enzyme.

All tumor cells exclusively express the embryonic M2 isoform of pyruvatekinase, suggesting PKM2 as a potential target for cancer therapy. PKM2is also expressed in adipose tissue and activated T-cells. Thus, themodulation (e.g. inhibition or activation) of PKM2 may be effective inthe treatment of, e.g., obesity, diabetes, autoimmune conditions, andproliferation-dependent diseases, e.g., benign prostatic hyperplasia(BPH). Current inhibitorss of pyruvate kinase are not selective, makingit difficult to treat disease related to pyruvate kinase function.

Furthermore, phosphotyrosine peptide binding to PKM2 leads to adissociation of FBP from PKM2 and conformational changes of PKM2 from anactive, tetrameric form to an inactive form. Compounds that bind to PKM2and lock the enzyme in the active confirmation will lead to the loss ofallosteric control of PKM2 needed for shunting biochemical intermediatesfrom glycolysis into biosynthesis of nucleotides and lipids. Thus, theactivation of PKM2 (i.e., activators of PKM2) can also inhibit thegrowth and proliferation of cancer cells, activated immune cells, andfat cells.

There is a continuing need for novel treatments of diseases such ascancer, diabetes, obesity, autoimmune conditions,proliferation-dependent diseases (e.g., BPH), and other diseases relatedto the function of pyruvate kinase (e.g., PKM2).

SUMMARY OF INVENTION

Described herein are compounds that modulate pyruvate kinase M2 (PKM2)and pharmaceutically acceptable salts, solvates, and hydrates thereof,for example, compounds that activate PKM2. Also provided arepharmaceutical compositions comprising a compound provided herewith andthe use of such compositions in methods of treating diseases andconditions that are related to pyruvate kinase function (e.g., PKM2function), including, e.g., cancer, diabetes, obesity, autoimmunedisorders, and benign prostatic hyperplasia (BPH).

In one embodiment, provided is a pharmaceutical composition comprising acompound or a pharmaceutically acceptable salt of formula (I):

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted aryl or optionally substituted heteroaryl; Lis a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—,—(CR^(c)R^(c))_(m)—OC(O)—, —(CR^(c)R^(c))_(m)C(O)—, —NR^(b)C(S)—, or—NR^(b)C(O)— (wherein the point of the attachment to R¹ is on theleft-hand side);

R¹ is selected from alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl; each of which is substituted with 0-5 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a), or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;each R^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or

two R^(c) taken together with the carbon atoms to which they areattached form an optionally substituted cycloalkyl;

-   -   each R^(d) is independently selected from halo, haloalkyl,        haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a),        —OC(O)R^(a), —C(O)OR^(a), —SR^(a), —NR^(a)R^(b) and —OR^(a), or        two R^(d) taken together with the carbon atoms to which they are        attached form an optionally substituted heterocyclyl;    -   n is 0, 1, or 2;    -   m is 1, 2 or 3;    -   h is 0, 1, 2; and    -   g is 0, 1 or 2.

In another embodiment, provided is a method for treating or preventing adisease, condition or disorder as described (e.g., treating) hereincomprising administering a compound provided herein, a pharmaceuticallyacceptable salt thereof, or pharmaceutical composition thereof.

In another embodiments, provided is a method of modulating (e.g.,increasing or decreasing) the level of PKM2 activity and/or glycolysis(e.g., modulating the endogenous ability of a cell in the patient todown regulate PKM2) in a patient in need thereof. The method comprisesthe step of administering an effective amount of a compound describedherein to the patient in need thereof, thereby modulating (e.g.,increasing or decreasing) the level of PKM2 activity and/or glycolysisin the patient. In some embodiments, a a compound or a compositiondescribed herein is used to maintain PKM2 in its active conformation oractivate pyruvate kinase activity in proliferating cells as a means todivert glucose metabolites into catabolic rather than anabolic processesin the patient.

In another embodiment, provided is a method of inhibiting cellproliferation in a patient in need thereof. The method comprises thestep of administering an effective amount of a compound described hereinto the patient in need thereof, thereby inhibiting cell proliferation inthe patient. E.g., this method can inhibiting growth of a transformedcell, e.g., a cancer cell, or generally inhibiting growth in aPKM2-dependent cell that undergoes aerobic glycolysis.

In another embodiment, provided is a method of treating a patientsuffering from or susceptible to a disease or disorder associated withthe function of PKM2 in a patient in need thereof. The method comprisesthe step of administering an effective amount of a compound describedherein to the patient in need thereof, thereby treating, preventing orameliorating the disease or disorder in the patient. In certainembodiment the modulator is provided in a pharmaceutical composition. Incertain embodiment, the method includes identifying or selecting apatient who would benefit from modulation (e.g., activation) of PKM2.E.g., the patient can be identified on the basis of the level of PKM2activity in a cell of the patient for treatment of cancer associatedwith PKM2 function. In another embodiment, the selected patient is apatient suffering from or susceptible to a disorder or diseaseidentified herein, e.g., a disorder characterized by unwanted cellgrowth or proliferation, e.g., cancer, obesity, diabetes,atherosclerosis, restenosis, and autoimmune diseases.

In another embodiment, the compound described herein is administered ata dosage and frequency sufficient to increase lactate production oroxidative phosphorylation.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1RRR represent a table of exemplary compounds and thecorresponding activity of the compound.

DETAILED DESCRIPTION

The details of construction and the arrangement of components set forthin the following description or illustrated in the drawings are notmeant to be limiting. Embodiments can be practiced or carried out invarious ways. Also, the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. Theuse of “including,” “comprising,” or “having,” “containing”,“involving”, and variations thereof herein, is meant to encompass theitems listed thereafter and equivalents thereof as well as additionalitems.

Compounds

Described herein are compounds and compositions that modulate PKM2, forexample, activate PKM2. Compounds that modulate PKM2, e.g., activatePKM2, can be used to treat disorders such as neoplastic disorders (e.g.,cancer) or fat related disorders (e.g., obesity).

In one embodiment, provided is a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted aryl or optionally substituted heteroaryl;

L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—,—(CR^(c)R^(c))_(m)—OC(O)—, —(CR^(c)R^(c))_(m)C(O)—, —NR^(b)C(S)—, or—NR^(b)C(O)— (wherein the point of the attachment to R¹ is on theleft-hand side);

R¹ is selected from alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl; each of which is substituted with 0-5 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a), or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;

each R^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl;

each R^(d) is independently selected from halo, haloalkyl, haloalkoxy,alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a),—C(O)OR^(a), —SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) takentogether with the carbon atoms to which they are attached form anoptionally substituted heterocyclyl;

n is 0, 1, or 2;

m is 1, 2 or 3;

h is 0, 1, 2; and

g is 0, 1 or 2. In certain embodiments, provided is a compound offormula (I) or a pharmaceutically acceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted bicyclic heteroaryl;

L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—,—(CR^(c)R^(c))_(m)—OC(O)—, —(CR^(c)R^(c))_(m)C(O)—, —NR^(b)C(S)—, or—NR^(b)C(O)—;

R¹ is selected from alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl; each of which is substituted with 0-5 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a) or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted cyclyl; eachR^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl;

each R^(d) is independently selected from halo, haloalkyl, haloalkoxy,alkyl, alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a),—C(O)OR^(a), —SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) takentogether with the carbon atoms to which they are attached form anoptionally substituted heterocyclyl;

n is 0, 1, or 2;

m is 1, 2 or 3;

h is 0, 1, 2; and

g is 0, 1 or 2. In some embodiments, h is 1. In some embodiments, h is2.

In some embodiments, g is 1. In some embodiments, g is 2.

In some embodiments, both h and g are 1. In some embodiments, h is 1 andg is 2. In some embodiments, g is 1 and h is 2.

In some embodiments, W, X, Y and Z are CH. In some embodiments, at leastone of W, X, Y and Z is N. In some embodiments, at least two of W, X, Yand Z are N. In some embodiments, at least three of W, X, Y and Z are N.

In some embodiments, W, X, Y, Z and the carbons to which they areattached form a pyridyl ring. In some embodiments, W, X, Y, Z and thecarbon atoms to which they are attached form a pyrimidyl ring. In someembodiments, W, X, Y, Z and the carbon atoms to which they are attachedform a pyridazinyl ring.

In some embodiments, W, X and Y are CH and Z is N.

In some embodiments, X, Y and Z are CH and W is N.

In some embodiments, D is NR^(b) and D¹ is a bond. In some embodiments,D is a bond and D¹ is NR^(b). In some embodiments, both D and D areNR^(b). In some embodiments, R^(b) is alkyl (e.g., methyl or ethyl). Insome embodiments, R^(b) is hydrogen (H).

In some embodiments, A is a 9-10 membered bicyclic heteroaryl (e.g.,quinazolinyl, quinoxalinyl, cinnolinyl, isoquinolyl, indolyl,benzoxazolyl, pyrrolopyridyl, pyrrolopyrimidyl, benzimidazolyl,benzthiazolyl, or benzoxazolyl). In some embodiments, A is aN-containing 9-10 membered bicyclic heteroaryl. In some embodiments, Ais optionally substituted quinazolinyl (e.g., 8-quinazolinyl or4-quinazolinyl), optionally substituted quinoxalinyl (e.g.,5-quinoxalinyl), optionally substituted quinolinyl (e.g., 4-quinolinylor 8-quinolinyl), optionally substituted cinnolinyl (e.g.,8-cinnolinyl), optionally substituted isoquinolinyl, optionallysubstituted indolyl (7-indolyl), optionally substituted benzoxazolyl(e.g., 7-benzoxazolyl), optionally substituted pyrrolopyridyl (e.g.,4-pyrrolopyridyl), optionally substituted pyrrolopyrimidyl (e.g.,4-pyrrolopyrimidyl), optionally substituted benzimidazolyl (e.g.,7-benzimidazolyl), optionally substituted benzthiazolyl (e.g.,4-benzthiazolyl, 2-methyl-4-benzthiazolyl or 7-benzthiazolyl), oroptionally substituted benzoxazolyl (e.g., 4-benzoxazolyl).

In some embodiments, A is optionally substituted with halo. In someembodiments, A is

In some embodiments, A is

In some embodiments, A is optionally substituted

In some embodiments, A is

In some embodiments, L is a bond.

In some embodiments, L is —(CR^(c)R^(c))_(m) and m is 1. In some aspectsof these embodiments, each R^(c) is hydrogen. In some aspects of theseembodiments, one R^(c) is alkyl (e.g., methyl or ethyl) and the otherR^(c) is hydrogen. In some aspects of these embodiments, one R^(c) ishalo (e.g., fluoro) and one R^(c) is hydrogen. In some aspects of theseembodiments, both R^(c) are halo (e.g., fluoro). In some aspects ofthese embodiments, one R^(c) is alkoxy (e.g., methoxy or ethoxy) and oneR^(c) is hydrogen. In some aspects of these embodiments, both R^(c) arealkoxy (e.g., methoxy or ethoxy). In some aspects of these embodiments,two R^(c) taken together with the carbon to which they are attached forma cycloalkyl (e.g., cyclopropyl).

In some embodiments, L is —(CR^(c)R^(c))_(m) and m is 2. In some aspectsof these embodiments, each R^(c) is hydrogen. In some aspects of theseembodiments, 1 R^(c) is alkyl (e.g., methyl or ethyl) and each of theother R^(c) are hydrogen. In some aspects of these embodiments, two R'staken together with the carbon to which they are attached form acycloalkyl (e.g., cyclopropyl) and each of the other two R's arehydrogen.

In some embodiments, L is —(CR^(c)R^(c))_(m) and m is 3. In some aspectsof these embodiments each R^(c) is hydrogen.

In some embodiments, L is —C(O)—.

In some embodiments, L is —O—C(O)—.

In some embodiments, L is NR^(b)C(O)— and R^(b) is H. In someembodiments, L is NR^(b)C(S)— and R^(b) is H.

In some embodiments, L is —(CR^(c)R^(c))_(m)C(O)— and m is 1. In someaspects of these embodiments, each R^(c) is hydrogen. In some aspects ofthese embodiments, one R^(c) is alkyl (e.g., methyl or ethyl) and oneR^(c) is hydrogen. In some aspects of these embodiments, both R^(c) arealkyl (e.g., methyl or ethyl).

In some embodiments, L is —(CR^(c)R^(c))_(m)C(O)— and m is 2. In someaspects of these embodiments, each R^(c) is hydrogen.

In some embodiments, L is —(CR^(c)R^(c))_(m)C(O)— and m is 3. In someaspects of these embodiments, each R^(c) is hydrogen.

In some embodiments, R¹ is alkyl substituted with 0-5 occurrences ofR^(d) (e.g., methyl, ethyl, n-propyl, i-propyl, or n-butyl). In someembodiments, R¹ is methyl, ethyl, n-propyl, i-propyl, or n-butyl. Insome embodiments, R¹ is ethyl or propyl (n-propyl or i-propyl). In someaspects of these embodiments, L is a bond, —CH₂—, —C(O)—, or —O(CO)—. Insome aspects of these embodiments, L is —O(CO)—.

In some embodiments, R¹ is alkyl substituted with 1 occurrence of R^(d)(e.g., methyl, ethyl, n-propyl, i-propyl, or n-butyl). In someembodiments, R¹ is methyl, ethyl, or n-propyl substituted with 1occurrence of R^(d). In some aspects of these embodiments, R^(d) is halo(e.g., fluorine or chlorine). In some aspects of these embodiments,R^(d) is —C(O)OR^(a). In some aspects of these embodiments, R^(a) isalkyl (e.g., methyl or ethyl). In some aspects of these embodiments, Lis —NHC(O)—.

In some embodiments, R¹ is alkyl substituted with 2 occurrences of R^(d)(e.g., methyl, ethyl, n-propyl, i-propyl, or n-butyl). In someembodiments, R¹ is methyl, ethyl, or n-propyl substituted with 2occurrences of R^(d). In some embodiments, R¹ is n-propyl substitutedwith 2 occurrences of R^(d). In some aspects of these embodiments, 1R^(d) is cyano and the other R^(d) is —NR^(a)R^(b). In some aspects ofthese embodiments, R^(a) and R^(b) are hydrogen. In some aspects ofthese embodiments, L is —CH₂—.

In some embodiments, R¹ is heteroaryl substituted with 0-5 occurrencs ofR^(d) (e.g., S-containing monocyclic heteroaryl, N-containing monocyclicheteroaryl or N-containing bicyclic heteroaryl). In some embodiments, R¹is a 5-8 membered monocyclic heteroaryl substituted with 0-5 occurrencsof R^(d) (e.g., thiophenyl, pyridyl, pyrimidyl or pyrazyl). In someembodiments, R¹ is pyridyl substituted with 0-5 occurrencs of R^(d)(e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), pyrimidyl substituted with0-5 occurrencs of R^(d) (e.g., 2-pyrimidyl or 5-pyrimidyl) or pyrazinylsubstituted with 0-5 occurrencs of R^(d) (e.g., 2-pyrazinyl). In someembodiments, R¹ is thiazolyl substituted with 0-5 occurrences of R^(d)(e.g., 2-thiazolyl or 5-thiazolyl). In some embodiments, R¹ is pyrimidylsubstituted with 0-5 occurrencs of R^(d) (e.g., 2-pyrimidyl). In someembodiments, R¹ is thiadiazolyl substituted with 0-5 occurrences ofR^(d) (e.g., 4-thiadiazolyl). In some embodiments, R¹ is pyrrolylsubstituted with 0-5 occurrences of R^(d) (e.g., 2-pyrrolyl). In someaspects of these embodiments, L is a bond, —CH₂—, —C(O)—, or —O(CO)—. Insome embodiments, R¹ is pyridyl (e.g., 2-pyridyl, 3-pyridyl or4-pyridyl).

In some embodiments, R¹ is pyridyl (e.g., 2-pyridyl, 3-pyridyl or4-pyridyl) substituted with 1 occurrence of R^(d). In some aspects ofthese embodiments, R^(d) is —OC(O)R^(a). In some aspects of theseembodiments, R^(d) is —OR^(a). In some aspects of these embodiments,R^(d) is —C(O)OR^(a). In some aspects of these embodiments, R^(d) isalkyl (e.g., methyl or ethyl). In some aspects of these embodiments,R^(d) is haloalkyl (e.g., trifluoromethyl). In some aspects of theseembodiments, R^(d) is halo (e.g., fluorine or chlorine). In some aspectsof these embodiments, R^(a) is alkyl (e.g., methyl or ethyl). In someaspects of these embodiments, L is —CH₂—. In some embodiments, R¹ ispyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl) substituted with 2occurrences of R^(d). In some aspects of these embodiments, one R^(d) is—C(O)OR^(a) and the other R^(d) is —OR^(a). In some aspects of theseembodiments, R^(a) is alkyl (e.g., methyl or ethyl). In some aspects ofthese embodiments, both R^(d) are halo (e.g., fluoro or chloro). In someaspects of these embodiments, L is —CH₂—.

In some embodiments, R¹ is pyrimidyl (e.g., 2-pyrimidyl or 5-pyrimidyl).In some aspects of these embodiments, L is a bond.

In some embodiments, R¹ is pyrimidyl (e.g., 2-pyrimidyl or 5-pyrimidyl)substituted with 1 occurrence of R^(d). In some aspects of theseembodiments, R^(d) is halo (e.g., fluoro or chloro).

In some embodiments, R¹ is pyrazinyl (e.g., 2-pyrazinyl). In someaspects of these embodiments, L is a bond.

In some embodiments, R¹ is thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, or5-thiazolyl). In some aspects of these embodiments, L is —C(O)—.

In some embodiments, R¹ is thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, or5-thiazolyl) substituted with 1 occurrences of R^(d). In some aspects ofthese embodiments, R^(d) is alkyl (e.g, methyl or ethyl). In someaspects of these embodiments, L is —C(O)—.

In some embodiments, R¹ is thiophenyl substituted with 0-5 occurrencs ofR^(d) (e.g., 2-thiophenyl). In some embodiments, R¹ is thiophenyl.

In some embodiments, R¹ is thiadiazolyl (e.g., 4-thiadiazolyl).

In some embodiments, R¹ is pyrrolyl (e.g., 2-pyrrolyl).

In some embodiments, R¹ is cycloalkyl substituted with 0-5 occurrencesof R^(d)(e.g., cyclopropyl, cyclopentyl or cyclohexyl). In someembodiments, R¹ is cyclopropyl. In some embodiments, R¹ is cyclohexyl.In some embodiments, R¹ is cyclopentyl. In some aspect of theseembodiments, L is —CH₂—C(O)—. In some embodiment, R¹ is aryl substitutedwith 0-5 occurrences of R^(d). In some aspects of these embodiments, Lis a bond, —CH₂—, —C(O)—, or —O(CO)—.

In some embodiments R¹ is aryl (e.g., phenyl). In some embodiments, R¹is phenyl. In some aspects of these embodiments, L is a bond, —CH₂—,—C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 1 occurrence ofR^(d). In some aspects of these embodiments, R^(d) is ortho substituted.In some aspects of these embodiments, R^(d) is meta substituted. In someaspects of these embodiments, R^(d) is para substituted. In some aspectsof these embodiments, R^(d) is halo (e.g., fluorine, bromine orchlorine). In some aspects of these embodiments, R^(d) is alkyl (e.g.,methyl, ethyl, isopropyl, t-butyl, n-butyl or n-pentyl). In some aspectsof these embodiments, R^(d) is haloalkyl (e.g., trifluoromethyl). Insome aspects of these embodiments, R^(d) is —OR^(a). In some aspects ofthese embodiments, R^(d) is —C(O)R^(a). In some aspects of theseembodiments, R^(d) is —SR^(a). In some aspects of these embodiments,R^(d) is —C(O)OR^(a). In some aspects of these embodiments, R^(d) iscyano. In some aspects of these embodiments, R^(d) is —NR^(a)R^(b). Insome aspects of these embodiments, R^(d) is haloalkoxy (e.g.,difluoromethoxy or trifluoromethoxy). In some aspects of theseembodiments, R^(d) is hydroxyl.

In some aspects of these embodiments, R^(d) is —OC(O)R^(a). In someaspects of these embodiments, R^(d) is alkynyl (e.g., 1-hexynyl). Insome aspects of these embodiments, R^(d) is haloalkyl (e.g.,trifluoromethyl). In some aspects of these embodiments, R^(a) is alkyl(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl orn-pentyl). In some aspects of these embodiments, R^(a) is hydroxyalkyl(e.g., 2-hydroxylethyl). In some aspects of these embodiments, R^(a) andR^(b) are alkyl (e.g., methyl or ethyl). In some aspects of theseembodiments, R^(a) is acyl (e.g., acetyl) and R^(b) is hydrogen. In someaspects of these embodiments, L is a bond, —CH₂—, —C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 2 occurrences ofR^(d). In some aspects of these embodiments, both R^(d) are halo (e.g.,fluorine or chlorine). In some aspects of these embodiments, both R^(d)are alkyl (e.g., methyl or ethyl). In some aspects of these embodiments,1 R^(d) is alkyl (e.g., methyl or ethyl) and the other is —OR^(a). Insome aspects of these embodiments, 1 R^(d) is halo (e.g., fluorine orchlorine) and the other R^(d) is —OR^(a). In some aspects of theseembodiments, both R^(d) are —OR^(a). In some aspects of theseembodiments, 1 R^(d) is halo (e.g., fluorine or chlorine) and the otherR^(d) is hydroxyl. In some aspects of these embodiments, 1 R^(d) is halo(e.g., fluorine or chlorine) and the other is haloalkyl (e.g.,trifluoromethyl). In some aspects of these embodiments, 1 R^(d) is—OR^(a) and the other R^(d) is —C(O)OR^(a). In some aspects of theseembodiments, 1 R^(d) is —OR^(a) and the other R^(d) is hydroxyl. In someaspects of these embodiments, 1 R^(d) is alkyl (e.g., methyl or ethyl)and the other R^(d) is hydroxyl. In some aspects of these embodiments,both R^(d) are hydroxyl. In some aspects of these embodiments, 1 R^(d)is halo (e.g., fluorine) and the other R^(d) is haloalkyl (e.g.,trifluoromethyl). In some aspects of these embodiments, both R^(d) arehydroxyl. In some aspects of these embodiments, one R^(d) is haloalkyl(e.g., trifluoromethyl) and the other R^(d) is alkyl (e.g., methyl). Insome aspects of these embodiments, two R^(d), together with the carbonatoms to which they are attached, form an optionally substitutedheterocyclyl. In some aspects of these embodiments, two R^(d), togetherwith the carbon atoms to which they are attached, form an optionallysubstituted 5-7 membered heterocyclyl. In some aspects of theseembodiments, two R^(d), together with the phenyl ring to which they areattached, form the following structure:

In some aspects of these embodiments, R^(a) is alkyl (e.g., methyl orethyl). In some aspects of these embodiments, L is a bond, —CH₂—,—C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 3 occurrences ofR^(d). In some aspects of these embodiments, 3 R^(d) are halo (e.g.,fluorine or chlorine). In some aspects of these embodiments, 2 R^(d) arehalo (e.g., fluorine or chlorine) and 1 R^(d) is hydroxyl. In someaspects of these embodiments, 1 R^(d) is halo (e.g., fluorine orchlorine), 1 R^(d) is alkyl (e.g., methyl) and 1 R^(d) is hydroxyl. Insome aspects of these embodiments, 3 R^(d) are alkyl (e.g., methyl orethyl). In some aspects of these embodiments, 2 R^(d) are alkyl (e.g.,methyl or ethyl) and 1 R^(d) is hydroxyl. In some aspects of theseembodiments, 2 R^(d) are halo (e.g., fluorine or chlorine) and 1 R^(d)is —OR^(a). In some aspects of these embodiments, R^(a) is alkyl (e.g.,methyl or ethyl). In some aspects of these embodiments, 1 R^(d) ishydroxyl and 2 R^(d) are —OR^(a). In some aspects of these embodiments,R^(a) is alkyl (e.g., methyl or ethyl). In some aspects of theseembodiments, 3 R^(d) are —OR^(a). In some aspects of these embodiments,3 R^(d) are halo (e.g., fluorine or chlorine). In some aspects of theseembodiments, R^(a) is alkyl (e.g., methyl or ethyl). In some aspects ofthese embodiments, L is a bond, —CH₂—, —C(O)—, or —O(CO)—.

In some embodiments, R¹ is phenyl substituted with 4 occurrences ofR^(d). In some aspects of these embodiments, 1 R^(d) is hydroxyl, 1R^(d) is alkyl (e.g., methyl or ethyl) and 2 R^(d) are —OR^(a). In someaspects of these embodiments, R^(a) is alkyl (e.g., methyl or ethyl). Insome aspects of these embodiments, L is a bond, —CH₂—, —C(O)—, or—O(CO)—.

In some embodiments, R¹ is heterocyclyl substituted with 0-5 occurrencesof R^(d).

In some embodiments, R¹ is tetrahydrofuranyl substituted with 0-5occurrences of R^(d)(e.g., 2-tetrahydrofuranyl or 3-tetrahydrofuranyl).In some aspects of these embodiments, R¹ is tetrahydrofuranyl (e.g.,2-tetrahydrofuranyl or 3-tetrahydrofuranyl). In some aspects of theseembodiments, L is —C(O)—.

In some embodiments, R¹ is azetidinyl substituted with 0-5 occurrencesof R^(d) (e.g., 3-azetidinyl). In some embodiments, R¹ is azetidinyl(e.g., 3-azetidinyl). In some embodiments, R¹ is azetidinyl (e.g.,3-azetidinyl) substituted with 1 occurrence of R^(d). In some aspects ofthese embodiments, R^(d) is alkyl (e.g., methyl or ethyl). In someaspects of these embodiments, L is —C(O)—.

In some embodiments, R¹ is 10-14 membered bicyclic aryl substituted with0-5 occurrences of R^(d). In some embodiments, R^(d) is naphthylsubstituted with 0-5 occurrences of R^(d).

In some embodiments, R^(d) is naphthyl.

In some embodiments, L is a bond, —(CR^(c)R^(c))_(m), —NR^(b)C(O)—,—(CR^(c)R)_(m)C(O)—, —C(O)—, or —O(CO)—.

In some embodiments, L is a bond and R¹ is alkyl, aryl or heteroarylsubstituted with 0-5 occurrences of R^(d). In some aspects of theseembodiments, alkyl, aryl or heteroaryl of R¹ is as described in any oneof the embodiments and aspects above.

In some embodiments, L is —(CR^(c)R^(c))_(m) and R¹ is cycloalkyl, aryl,heteroaryl or heterocyclyl substituted with 0-5 occurrences of R^(d). Insome aspects of these embodiments, cycloalkyl, aryl, heteroaryl orheterocyclyl of R¹ is as described in any one of the embodiments andaspects above.

In some embodiments, L is —NR^(b)C(O)— and R^(b) is hydrogen; and R¹ isaryl substituted with 0-5 occurrences of R^(d). In some aspects of theseembodiments, aryl of R¹ is as described in any one of the embodimentsand aspects above. In some embodiments, L is —(CR^(c)R^(c))_(m)C(O)— andR¹ is cycloalkyl, aryl or heteroaryl substituted with 0-5 occurrencs ofR^(d). In some aspects of these embodiments, cycloalkyl, aryl, orheteroaryl of R¹ is as described in any one of the embodiments andaspects above.

In some embodiments, L is —C(O)— and R¹ is aryl, alkyl, or heteroarylsubstituted with 0-5 occurrencs of R^(d). In some aspects of theseembodiments, aryl, alkyl, or heteroaryl of R¹ is as described in any oneof the embodiments and aspects above.

In some embodiments, L is —OC(O)— and R¹ is alkyl, aryl or heterocyclylsubstituted with 0-5 occurrences of R^(d). In some aspects of theseembodiments, alkyl, aryl, or heterocyclyl of R¹ is as described in anyone of the embodiments and aspects above.

In some embodiments, L is —(CR^(c)R^(c))_(m)—OC(O)— and R¹ isheterocyclyl or cycloalkyl substituted with 0-5 occurrences of R^(d). Insome aspects of these embodiments, heterocyclyl or cycloalkyl of R¹ isas described in any one of the embodiments and aspects above.

In some embodiments, n is 0. In some embodiments, n is 1.

In some embodiments, R³ is alkyl (e.g., methyl or ethyl). In someembodiments, R³ is —OR^(a). In some aspects of these embodiments, R^(a)is alkyl (e.g., methyl or ethyl). In some embodiments, R³ is halo (e.g.,fluorine or chlorine). In some embodiments, R³ is hydroxyl. In someembodiments, R³ is haloalkyl (e.g., trifluoromethyl).

In some embodiments, n is 2.

In some embodiments, two adjacent R³ taken together with the carbonatoms to which they are attached form a heterocyclyl ring. In someembodiments, both R³ are —OR^(a). In some embodiments, two adjacent R³taken together with the carbon atoms to which they are attached form

In certain embodiments, a compound is of formula (II) or apharmaceutical acceptable salt thereof:

wherein L, R¹, R³, R^(a), R^(b), R^(c), R^(d), Y, Z, m, h and g are asdefined above in formula (I) or any one of the embodiments or aspectsdescribed herein.

In certain embodiments, A is aryl (e.g., phenyl or naphthyl) optionallysubstituted with 1 or 2 occurrences of R², wherein each R² isindependently selected from halo, haloalkyl, aryl, heteroaryl, alkyl,—OR^(a), —COOR^(c), or —CONR^(c)R^(c); and D, D, L, R¹, R³, R^(a),R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined above informula (I) or any one of the embodiments or aspects described herein.In some aspect of these embodiments, D and D¹ are N. In some aspect ofthese embodiments, at least one of W, X, Y and Z is N. In some aspect ofthese embodiments, one of W, Y and Z is N; h is 1 and g is 1.

In certain embodiments, A is heteroaryl (e.g., N-containing monocyclicheteroaryl or N-containing bicyclic heteroaryl); and D, D¹, L, R¹, R³,R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as definedabove in formula (I) or any one of the embodiments or aspects describedherein.

In some embodiments, A is a 5-8 membered monocyclic heteroaryl (e.g.,pyridyl, pyrimidyl, or pyrazyl); and D, D¹, L, R¹, R³, R^(a), R^(b),R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined above in formula(I) or any one of the embodiments or aspects described herein. In someembodiments, A is a 5-8 membered N-containing monocyclic heteroaryl; andD, D¹, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and gare as defined above in formula (I) or any one of the embodiments oraspects described herein. In some embodiments, A is optionallysubstituted pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl),optionally substituted pyrimidyl (e.g., 2-pyrimidyl or 5-pyrimidyl), oroptionally substituted pyrazyl (e.g., 2-pyrazyl); and L, R¹, R³, R^(a),R^(b), R^(c), R^(d), Y, m, h and g are as defined above in formula (I)or any one of the embodiments or aspects described herein.

In some embodiments, A is substituted with 1 occurrence of R²; and D, D,L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are asdefined above in formula (I) or any one of the embodiments or aspectsdescribed herein. In some aspects of these embodiments, R² is alkyl(e.g., methyl or ethyl). In some aspects of these embodiments, R² ishalo. In some aspects of these embodiments, R² is fluorine (F). In someaspects of these embodiments, R² is bromine (Br). In some aspects ofthese embodiments, R² is chlorine (Cl). In some aspects of theseembodiments, R² is —OR^(a). In some aspects of these embodiments, R^(a)is alkyl (e.g., methyl).

In some embodiments, A is substituted with 2 occurrences of R²; and D,D¹, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g areas defined above in formula (I) or any one of the embodiments or aspectsdescribed herein. In some aspects of these embodiments, both R² are halo(e.g., fluorine or fluorine and chlorine). In some aspects of theseembodiments, both R² are alkyl (e.g, methyl). In some aspects of theseembodiments, both R² are —OR^(a). In some aspects of these embodiments,one R² is halo and the other is —OR^(a). In some aspects of theseembodiments, one R² is bromine (BR) and the other is —OR^(a). In someaspects of these embodiments, one R² is chlorine (Cl) and the other is—OR^(a). In some aspects of these embodiments, one R² is fluorine (F)and the other is —OR^(a). In some aspects of these embodiments, R^(a) isalkyl (e.g., methyl or ethyl). In some aspects of these embodiments,both R² are —OR^(a). In some aspects of these embodiments, two —OR^(a)taken together with the carbon atoms to which they are attached form aheterocyclyl. In some embodiments, A is

and D, D¹, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, hand g are as defined above in formula (I) or any one of the embodimentsor aspects described herein.

In another embodiment, provided is a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR^(b);

A is optionally substituted aryl or optionally substituted heteroaryl;

L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—, or —C(O)NR^(b)—;

R¹ is independently selected from alkyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl; each of which are substituted with 0-3 occurrences ofR^(d);

each R³ is independently selected from halo, haloalkyl, alkyl, hydroxyland —OR^(a) or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted cyclyl;

each R^(a) is independently selected from alkyl and haloalkyl;

each R^(b) is independently selected from hydrogen and alkyl;

each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl;

each R^(d) is independently selected from halo, haloalkyl, alkyl, nitro,cyano and —OR^(a), or two R^(d) taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;

n is 0, 1, or 2;

m is 1, 2 or 3;

h is 0, 1, 2; and

g is 0, 1 or 2. In some aspects of this embodiment, A, D, D, L, R¹, R³,R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined inany one of the embodiments or aspects described herein.

In another embodiment, provided is a compound of formula (I) or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof:

wherein:

W, X, Y and Z are each independently selected from CH or N;

D and D¹ are independently selected from a bond or NR;

A is optionally substituted aryl or optionally substituted heteroaryl;

R¹ is independently selected from alkyl, optionally substituted aryl,and optionally substituted heteroaryl;

each R³ is independently selected from halo, haloalkyl, alkyl, and—OR^(a);

each R^(a) is independently selected from alkyl, haloalkyl andoptionally substituted heteroaryl;

each R^(b) is independently alkyl;

each R^(c) is independently selected from hydrogen or alkyl;

n is 0, 1, or 2;

h is 0, 1, 2; and

g is 0, 1 or 2. In some aspects of this embodiment, A, D, D, L, R¹, R³,R^(a), R^(b), R^(c), R^(d), X, Y, Z, W, n, m, h and g are as defined inany one of the embodiments or aspects described herein.

In another embodiment, provided is a compound or pharmaceuticallyacceptable salt of formula (Ib) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Ib):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), W, X, Z, m, h and gare as defined above in formula (I) or any one of the embodiments oraspects described herein.

In some embodiments, X, W and Z are CH. In some embodiments, one of X, Wand Z is N and the other two of X, W and Z are CH.

In another embodiment, provided is a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Ic) or a pharmaceutical composition comprising a compound orpharmaceutically acceptable salt of formula (Ic):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), W, X, Y, m, h and gare as defined above in formula (I) or any one of the embodiments oraspects described herein.

In some embodiments, X, Y and W are CH. In some embodiments, one of X, Yand W is N and the other two of X, Y and W are CH.

In another embodiment, provided is a compound or pharmaceuticallyacceptable salt of formula (Id) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Id):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), Y, Z, m, h and g areas defined above in formula (I) or any one of the embodiments or aspectsdescribed herein.

In some embodiments, Y and Z are CH. In some embodiments, one of Y and Zis N and one of Y and Z is CH.

In another embodiment, provided is a compound or pharmaceuticallyacceptable salt of formula (Ie) or a pharmaceutical compositioncomprising a compound or pharmaceutically acceptable salt of formula(Ie):

wherein A, L, R¹, R³, R^(a), R^(b), R^(c), R^(d), W, X, Y, Z, m, h and gare as defined above in formula (I) or any one of the embodiments oraspects described herein.

In certain embodiments, exemplary compounds of Formula I include thecompounds described in FIG. 1 and in the Examples. In some embodiments,a compound described herein modulates PKM2 by interacting (e.g.,binding) with the FBP binding pocket. For example, a compound describedherein can compete with FBP binding in PKM2.

In some embodiments a compound described herein has one or moreproperties described herein, e.g., one or more of the followingproperties: it is an allosteric modulator (e.g., activator); itmodulates the release of FBP (e.g., promotes); it is a modulator (e.g.,agonist) of FBP, e.g., an agonist which binds with a lower, about thesame, or higher affinity than does FBP; it modulates (e.g., promotes)the dissolution of tetrameric PKM2; it modulates (e.g., promotes) theassembly of tetrameric PKM2; it selectively modulates (e.g., activates)PKM2 over at least one other isoform of PK, e.g., it is selective forPKM2 over PKR, PKM1, or PKL; is has an affinity for PKM2 which isgreater than its affinity for at least one other isoform of PK, e.g.,PKR, PKM1, or PKL.

In another embodiment, the activator of PKM2 utilized in the methods andcompositions described herein operates by or has one or more of thefollowing mechanisms or properties:

-   -   a. it is an allosteric activator of PKM2;    -   b. it modulates (e.g., stabilizes) the binding of FBP in a        binding pocket of PKM2;    -   c. it modulates (e.g., promotes) the release of FBP from a        binding pocket of PKM2;    -   d. it is a modulator (e.g., an agonist), e.g., an analog, of        FBP, e.g., an agonist which binds PKM2 with a lower, about the        same, or higher affinity than does FBP;    -   e. it modulates (e.g., promotes) the dissolution of tetrameric        PKM2;    -   f. it modulates (e.g., promotes) the assembly of tetrameric        PKM2;    -   g. it modulates (e.g., stabilizes) the tetrameric conformation        of PKM2;    -   h. it modulates (e.g., promotes) the binding of a        phosphotyrosine containing polypeptide to PKM2;    -   i. it modulates (e.g., promotes) the ability of a        phosphotyrosine containing polypeptide to induce release of FBP        from PKM2, e.g., by inducing a change in the conformation of        PKM2, e.g., in the position of Lys 433, thereby hindering the        release of FBP;    -   k. it binds to or changes the position of Lys 433 relative to        the FBP binding pocket;    -   l. it selectively modulates (e.g., activates) PKM2 over at least        one other isoform of PK, e.g., it is selective for PKM2 over one        or more of PKR, PKM1, or PKL;    -   m. it has an affinity for PKM2 which is greater than its        affinity for at least one other isoform of PK, e.g., PKR, PKM1,        or PKL.

A compound described herein may be tested for its ability to activatePKM2. For simplicity, the activation activity of these compounds isrepresented as an AC₅₀ in FIG. 1 and throughout the application.Exemplary compounds are shown in FIG. 1. As shown in FIG. 1, “A” refersto an activator of PKM2 with an EC₅₀<100 nM. “B” refers to an activatorof PKM2 with an EC₅₀ between 100 nM and 500 nM. “C” refers to anactivator of PKM2 with an EC₅₀ between 500 nM and 1000 nM. “D” refers toan activator of PKM2 with an EC₅₀ between 1 μM and 10 μM. “E” refers todata that is not available.

The compounds described herein can be made using a variety of synthetictechniques.

Scheme 1 above is an exemplary scheme that depicts a representativesynthesis of certain compounds described herein. Sulfonyl chloride 1 isreacted with amine 2 under standard coupling conditions to produce ester3. Hydrolysis of 3 using lithium hydroxide generates carboxylic acid 4.Piperazine (5) is with the appropriate bromide under standard palladiumcoupling conditions to provide 7. Carboxylic acid 4 is then treated withpiperazine derivative 7 to produce final compound 8.

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Additionally, the various synthetic steps maybe performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P.G.M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds provided herein may contain one or more asymmetric centersand thus occur as racemates and racemic mixtures, single enantiomers,individual diastereomers and diastereomeric mixtures. All such isomericforms of these compounds are expressly included within the scope. Unlessotherwise indicated when a compound is named or depicted by a structurewithout specifying the stereochemistry and has one or more chiralcenters, it is understood to represent all possible stereoisomers of thecompound. The compounds provided herewith may also contain linkages(e.g., carbon-carbon bonds) or substituents that can restrict bondrotation, e.g. restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded.

The compounds provided herein (e.g. of Formula I) may also comprise oneor more isotopic substitutions. For example, H may be in any isotopicform, including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may bein any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in anyisotopic form, including ¹⁶O and ¹⁸O; and the like. The compoundsprovided herein may also be represented in multiple tautomeric forms, insuch instances, expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented (e.g., alkylation of a ring system may result in alkylationat multiple sites; all such reaction products are expressly included).All such isomeric forms of such compounds are expressly included. Allcrystal forms of the compounds described herein are expressly included.

The compounds provided herein include the compounds themselves, as wellas their salts and their prodrugs, if applicable. A salt, for example,can be formed between an anion and a positively charged substituent(e.g., amino) on a compound described herein. Suitable anions includechloride, bromide, iodide, sulfate, nitrate, phosphate, citrate,methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt canalso be formed between a cation and a negatively charged substituent(e.g., carboxylate) on a compound described herein. Suitable cationsinclude sodium ion, potassium ion, magnesium ion, calcium ion, and anammonium cation such as tetramethylammonium ion. Examples of prodrugsinclude esters and other pharmaceutically acceptable derivatives, which,upon administration to a subject, are capable of providing activecompounds.

The compounds provided herein may be modified by appending appropriatefunctionalities to enhance selected biological properties, e.g.,targeting to a particular tissue. Such modifications are known in theart and include those which increase biological penetration into a givenbiological compartment (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

In an alternate embodiment, the compounds described herein may be usedas platforms or scaffolds that may be utilized in combinatorialchemistry techniques for preparation of derivatives and/or chemicallibraries of compounds. Such derivatives and libraries of compounds havebiological activity and are useful for identifying and designingcompounds possessing a particular activity. Combinatorial techniquessuitable for utilizing the compounds described herein are known in theart as exemplified by Obrecht, D. and Villalgrodo, J. M.,Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries, Pergamon-Elsevier ScienceLimited (1998), and include those such as the “split and pool” or“parallel” synthesis techniques, solid-phase and solution-phasetechniques, and encoding techniques (see, for example, Czarnik, A. W.,Curr. Opin. Chem. Bio., (1997) 1, 60. Thus, one embodiment relates to amethod of using the compounds described herein for generatingderivatives or chemical libraries comprising: 1) providing a bodycomprising a plurality of wells; 2) providing one or more compoundsidentified by methods described herein in each well; 3) providing anadditional one or more chemicals in each well; 4) isolating theresulting one or more products from each well. An alternate embodimentrelates to a method of using the compounds described herein forgenerating derivatives or chemical libraries comprising: 1) providingone or more compounds described herein attached to a solid support; 2)treating the one or more compounds identified by methods describedherein attached to a solid support with one or more additionalchemicals; 3) isolating the resulting one or more products from thesolid support. In the methods described above, “tags” or identifier orlabeling moieties may be attached to and/or detached from the compoundsdescribed herein or their derivatives, to facilitate tracking,identification or isolation of the desired products or theirintermediates. Such moieties are known in the art. The chemicals used inthe aforementioned methods may include, for example, solvents, reagents,catalysts, protecting group and deprotecting group reagents and thelike. Examples of such chemicals are those that appear in the varioussynthetic and protecting group chemistry texts and treatises referencedherein.

Definitions

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁-C₁₂ alkyl indicates that the group may have from1 to 12 (inclusive) carbon atoms in it. The term “haloalkyl” refers toan alkyl in which one or more hydrogen atoms are replaced by halo, andincludes alkyl moieties in which all hydrogens have been replaced byhalo (e.g., perfluoroalkyl). The terms “arylalkyl” or “aralkyl” refer toan alkyl moiety in which an alkyl hydrogen atom is replaced by an arylgroup. Aralkyl includes groups in which more than one hydrogen atom hasbeen replaced by an aryl group. Examples of “arylalkyl” or “aralkyl”include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl,and trityl groups.

The term “alkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—,and —CH₂CH₂CH₂—.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and having one or more double bonds.Examples of alkenyl groups include, but are not limited to, allyl,propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the doublebond carbons may optionally be the point of attachment of the alkenylsubstituent. The term “alkynyl” refers to a straight or branchedhydrocarbon chain containing 2-12 carbon atoms and characterized inhaving one or more triple bonds. Examples of alkynyl groups include, butare not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triplebond carbons may optionally be the point of attachment of the alkynylsubstituent.

The terms “alkylamino” and “dialkylamino” refer to —NH(alkyl) and—NH(alkyl)₂ radicals respectively. The term “aralkylamino” refers to a—NH(aralkyl) radical. The term alkylaminoalkyl refers to a(alkyl)NH-alkyl-radical; the term dialkylaminoalkyl refers to a(alkyl)₂N-alkyl-radical The term “alkoxy” refers to an —O-alkyl radical.The term “mercapto” refers to an SH radical. The term “thioalkoxy”refers to an —S-alkyl radical. The term thioaryloxy refers to an —S-arylradical.

The term “aryl” refers to a monocyclic, bicyclic, or tricyclic aromatichydrocarbon ring system, wherein any ring atom capable of substitutioncan be substituted (e.g., by one or more substituents). Examples of arylmoieties include, but are not limited to, phenyl, naphthyl, andanthracenyl.

The term “cycloalkyl” as employed herein includes cyclic, bicyclic,tricyclic, or polycyclic non-aromatic hydrocarbon groups having 3 to 12carbons. Any substitutable ring atom can be substituted (e.g., by one ormore substituents). The cycloalkyl groups can contain fused or spirorings. Fused rings are rings that share a common carbon atom. Examplesof cycloalkyl moieties include, but are not limited to, cyclopropyl,cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

The terms “heterocyclyl” or “heterocyclic group” refer to 3- to14-membered non-aromatic ring structures (e.g., 3- to 14-membered rings,more preferably 3- to 7-membered rings), whose ring structures includeone to four heteroatoms independently selected from O, N and S. Theheterocyclyl or heterocyclic groups can contain fused or spiro rings.Heterocycles can also be polycycles, with each group having, e.g., 5-7ring members. The term “heterocyclyl” or “heterocyclic group” includessaturated and partially saturated heterocyclyl structures. The term“heteroaryl” refers to a 5-14 membered (i.e., a 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic) aromatic ringsystem having 1-3 ring heteroatoms if monocyclic, 1-6 ring heteroatomsif bicyclic, or 1-9 ring heteroatoms if tricyclic, said ring heteroatomsindependently selected from O, N, and S (e.g., 1-3, 1-6, or 1-9 ringheteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic,respectively). Any substitutable ring atom can be substituted (e.g., byone or more substituents). Heterocyclyl and heteroaryl groups include,for example, thiophene, thianthrene, furan, pyran, isobenzofuran,chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole,isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine,indolizine, isoindole, indole, indazole, purine, quinolizine,isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline,quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine,acridine, pyrimidine, phenanthroline, phenazine, phenarsazine,phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane,oxazole, piperidine, piperazine, morpholine, lactones, lactams such asazetidinones and pyrrolidinones, sultams, sultones, and the like. Theheterocyclic or heteroaryl ring can be substituted at one or morepositions with such substituents as described herein, as for example,halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino,nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate,carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde,ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN,or the like.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocycle group.

The term “cycloalkenyl” refers to partially unsaturated, nonaromatic,monocyclic, bicyclic, or tricyclic hydrocarbon groups having 5 to 12carbons, preferably 5 to 8 carbons. The unsaturated carbon mayoptionally be the point of attachment of the cycloalkenyl substituent.

Any substitutable ring atom can be substituted (e.g., by one or moresubstituents). The cycloalkenyl groups can contain fused or spiro rings.Fused rings are rings that share a common carbon atom. Examples ofcycloalkenyl moieties include, but are not limited to, cyclohexenyl,cyclohexadienyl, or norbornenyl.

The term “heterocycloalkenyl” refers to a partially saturated,nonaromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, saidheteroatoms independently selected from O, N, and S (e.g., 1-3, 1-6, or1-9 ring heteroatoms of N, O, or S if monocyclic, bicyclic, ortricyclic, respectively). The unsaturated carbon or the heteroatom mayoptionally be the point of attachment of the heterocycloalkenylsubstituent. Any substitutable ring atom can be substituted (e.g., byone or more substituents).

The heterocycloalkenyl groups can contain fused rings. Fused rings arerings that share a common carbon atom. Examples of heterocycloalkenylinclude but are not limited to tetrahydropyridyl and dihydropyranyl.

The terms “hetaralkyl” and “heteroaralkyl”, as used herein, refers to analkyl group substituted with a heteroaryl group. The ring heteroatoms ofthe compounds provided herein include N—O, S(O), and S(O)₂.

The term “oxo” refers to an oxygen atom, which forms a carbonyl whenattached to carbon, an N-oxide when attached to nitrogen, and asulfoxide or sulfone when attached to sulfur.

The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl,arylcarbonyl, heterocyclylcarbonyl, or heteroarylcarbonyl substituent,any of which may be further substituted (e.g., by one or moresubstituents).

The term “substituents” refers to a group “substituted” on an alkyl,cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl,cycloalkenyl, aryl, or heteroaryl group at any substitutable atom ofthat group. Any substitutable atom can be substituted. Unless otherwisespecified, such substituents include, without limitation, alkyl (e.g.,C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 straight or branchedchain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF₃),aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl,alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g.,perfluoroalkoxy such as OCF₃), halo, hydroxy, carboxy, carboxylate,cyano, nitro, amino, alkyl amino, SO₃H, sulfate, phosphate,methylenedioxy (—O—CH₂—O— wherein oxygens are attached to vicinalatoms), ethylenedioxy, oxo (not a substituent on heteroaryl), thioxo(e.g., C=S) (not a substituent on heteroaryl), imino (alkyl, aryl,aralkyl), S(O)nalkyl (where n is 0-2), S(O)_(n) aryl (where n is 0-2),S(O)_(n) heteroaryl (where n is 0-2), S(O)_(n) heterocyclyl (where n is0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl,aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl), amide (mono-, di-, alkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide(mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof).In one aspect, the substituents on a group are independently any onesingle, or any subset of the aforementioned substituents. In anotheraspect, a substituent may itself be substituted with any one of theabove substituents.

The term “selective” is meant at least 2-fold, 3-fold, 4-fold, 5-fold,6-fold, or 10-fold greater modulation (e.g., activation) of PKM2 thanPKM1.

The term “activator” as used herein means an agent that (measurably)increases the activity of a pyruvate kinase (e.g., PKM2) or causespyruvate kinase (e.g., PKM2) activity to increase to a level that isgreater than PKM2's basal levels of activity. For example, the activatormay mimic the effect caused by a natural ligand (e.g., FBP). Theactivator effect caused by a compound provided herein may be to thesame, or to a greater, or to a lesser extent than the activating effectcaused by a natural ligand, but the same type of effect is caused. Acompound provided herein can be evaluated to determine if it is anactivator by measuring either directly or indirectly the activity of thepyruvate kinase when subjected to said compound. The activity of acompound provided herein can be measured, for example, against a controlsubstance. In some instances, the activity measured of the test compoundis for activation of PKM2. The activity of PKM2 can be measured, forexample, by monitoring the concentration of a substrate such as ATP orNADH.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

Methods of Evaluating Compounds

The compounds described herein can be evaluated for ability to modulatePKM2 (e.g., activate PKM2) by methods known in the art. In someembodiments, compounds described herein are evaluated for ability tomodulate PKM2 (e.g. activate PKM2) in serine deficient conditions. Insome embodiments, exemplary methods include contacting the compound witha cell-based assay which allows assessment of the ability to modulate(e.g., activate) PKM2. E.g., the candidate compound can be contactedwith a cell and measuring the consumption of oxygen or production oflactate. A change in cellular phosphoenolpyruvate, a change inglycerol-phosphate, a change in ribose or deoxyribose, a change in lipidsynthesis, or a change in glucose conversion to lipid or nucleic acidsor amino acids or protein can also be used to evaluate a compound forits ability to modulate PKM2 (e.g., activate PKM2). The evaluation couldalso include measuring a change in pyruvate or a determination of analteration in mitochondrial membrane potential, e.g., as measured byfluorescent potentiometric dyes.

The activity of the PKM enzyme measured in the screening/testing assaymay be measured by, e.g., monitoring the concentration of a substrate(e.g., ATP or NADH) present in the reaction mixture. Pyruvate, producedby the enzymatic activity of pyruvate kinase, is converted into lactateby lactate dehydrogenase, which requires the consumption of NADH(NADH→NAD+). Thus, the activity of PKM2 can be indirectly measured bymonitoring the consumption of NADH through, e.g., fluorescence assays.Additionally, the activity of the PKM2 enzyme can be directly monitoredby measuring the production of ATP, as ATP is produced whenphosphoenolpyruvate is converted to pyruvate. Methods for monitoring theamount of substrate in a reaction mixture include, e.g., absorbance,fluorescence, Raman scattering, phosphorescence, luminescence,luciferase assays, and radioactivity.

The screening procedure requires the presence of specific components inthe reaction mixture. Components utilized in the assay include, e.g., anucleoside diphosphate (e.g., ADP), phosphoenolpyruvate, NADH, lactatedehydrogenase, FBP, a reducing agent (e.g., dithiothreitol), a detergent(e.g., Brij 35), glycerol, and a solvent (e.g., DMSO). Exemplaryreaction conditions are found in Table 1.

TABLE 1 Amount in Component of Reaction Condition Activation Assay ADP0.1-5.0 mM Phosphoenolpyruvate 0.1-5.0 mM NADH 10-1000 μM Lactatedehydrogenase 0.1-10 units Fructose-1,6-bisphosphate 0 DTT 0.1-50 mMBrij 35 0.01-1% Glycerol 0.1-10% Pyruvate Kinase M2 (used for screen)1-100 pg DMSO 1-10%

In some embodiments, a compound such as a compound described herein, canbe evaluated in a cellular/ex vivo assay. For example, a cell is treatedwith a compound described herein (i.e., a PKM2 activator), and thecompound is evaluated, for example for its ability to enter the cell andbind to PKM2, inducing an activated conformation of PKM2. The excessunbound compound can then be washed away with PBS, and the cells lysed,for example, by snap-freezing on dry ice, followed by addition of adetergent-containing lysis buffer. The lysate, in which activated PKM2remains intact, can then be removed and added to a chemical cocktailincluding the chemicals necessary to measure pyruvate kinase activity.The assay can be coupled to another assay such as an assay that iscoupled to the LDHa enzyme. The amount of pyruvate kinase activity thatis measured can then be normalized to the total protein content in thelysate, and related to the concentration of PKM2 activator that wasadded to the cell. This can allow an AC₅₀ (concentration at which PKM2is activated 50%) value to be derived. The total fold-increase inactivity over mock-treated cells can also be calculated, and the“maximum level of activation” can be used to distinguish betweencompounds that fully activate PKM2 and compounds that can only partiallyactivate PKM2. In the case of measuring PKM2 activity from tissue (forexample, in a cell tumor), animals harboring the tissue/tumor ofinterest can be dosed with a compound. After a specified period of timein which exposure has been achieved in the target tissue/tumor ofinterest, the tissue/tumor can then be harvested from the animal,snap-frozen, and then lysed and homogenized. The amount of pyruvatekinase activity in this lysate can then be quantitated as describedabove.

PKM1 and PKM2 for use in the screening/testing methods described hereinmay be produced by any method known in the art for expression ofrecombinant proteins. For example, nucleic acids that encode the desiredpolypeptide may be introduced into various cell types or cell-freesystems for expression. Eukaryotic (e.g., COS, HEK293T, CHO, and NIHcell lines) and prokaryotic (e.g., E. coli) expression systems may begenerated in which a PKM sequence is introduced into a plasmid or othervector, which is then used to transform living cells.

Constructs in which the PKM cDNA contains the entire open reading frame,or biologically active fragment thereof, are inserted in the correctorientation into an expression plasmid and may be used for proteinexpression. Prokaryotic and eukaryotic expression systems allow for theexpression and recovery of fusion proteins in which the PKM protein iscovalently linked to a tag molecule on either the amino terminal orcarboxy terminal side, which facilitates identification and/orpurification. Examples of tags that can be used include hexahistidine,HA, FLAG, and c-myc epitope tags. An enzymatic or chemical cleavage sitecan be engineered between the PKM protein and the tag molecule so thatthe tag can be removed following purification.

Compounds useful as PKM2 activators are those demonstrate specificityand activation of PKM2 enzyme in the absence of FBP to a level greaterthan that of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 99, or 100% in the presence of FBP. Furthermore, compoundscan be evaluated in the presence or absence of a phosphotyrosinepeptide. Phosphotyrosine peptide binding to PKM2 leads to a dissociationof FBP from PKM2 and conformational changes of PKM2 from an active,tetrameric form to an inactive form. Compounds that bind to PKM2 andlock the enzyme in the active confirmation even in the presence of aphosphotyrosine peptide will lead to the loss of allosteric control ofPKM2 needed for shunting the biochemical intermediates from glycolysisinto biosynthesis of other intermediates. This, in turn, will lead toinhibition of growth of cancer cells, activated immune cells and fatcells.

Methods of Treatment

In one embodiment, provided is a method for treating or preventing adisease, condition or disorder as described herein (e.g., treating)comprising administering a compound, a pharmaceutically acceptable saltof a compound or pharmaceutical composition comprising a compounddescribed herein (e.g., a compound of formula (I), (I-a), (II) or inFIG. 1).

The compounds and compositions described herein can be administered tocells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., invivo, to treat, prevent, and/or diagnose a variety of disorders,including those described herein below.

As used herein, the term “treat” or “treatment” is defined as theapplication or administration of a compound, alone or in combinationwith, a second compound to a subject, e.g., a patient, or application oradministration of the compound to an isolated tissue or cell, e.g., cellline, from a subject, e.g., a patient, who has a disorder (e.g., adisorder as described herein), a symptom of a disorder, or apredisposition toward a disorder, with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve or affect thedisorder, one or more symptoms of the disorder or the predispositiontoward the disorder (e.g., to prevent at least one symptom of thedisorder or to delay onset of at least one symptom of the disorder).

As used herein, an amount of a compound effective to treat a disorder,or a “therapeutically effective amount” refers to an amount of thecompound which is effective, upon single or multiple dose administrationto a subject, in treating a cell, or in curing, alleviating, relievingor improving a subject with a disorder beyond that expected in theabsence of such treatment.

As used herein, an amount of a compound effective to prevent a disorder,or a “a prophylactically effective amount” of the compound refers to anamount effective, upon single- or multiple-dose administration to thesubject, in preventing or delaying the occurrence of the onset orrecurrence of a disorder or a symptom of the disorder.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patienthaving a disorder, e.g., a disorder described herein or a normalsubject. The term “non-human animals” includes all vertebrates, e.g.,non-mammals (such as chickens, amphibians, reptiles) and mammals, suchas non-human primates, domesticated and/or agriculturally usefulanimals, e.g., sheep, dog, cat, cow, pig, etc.

Neoplastic Disorders

A compound or composition described herein can be used to treat aneoplastic disorder. A “neoplastic disorder” is a disease or disordercharacterized by cells that have the capacity for autonomous growth orreplication, e.g., an abnormal state or condition characterized byproliferative cell growth. Exemplary neoplastic disorders include:carcinoma, sarcoma, metastatic disorders (e.g., tumors arising fromprostate, colon, lung, breast and liver origin), hematopoieticneoplastic disorders, e.g., leukemias, metastatic tumors. Prevalentcancers include: breast, prostate, colon, lung, liver, and pancreaticcancers. Treatment with the compound may be in an amount effective toameliorate at least one symptom of the neoplastic disorder, e.g.,reduced cell proliferation, reduced tumor mass, etc.

The disclosed methods are useful in the prevention and treatment ofcancer, including for example, solid tumors, soft tissue tumors, andmetastases thereof. The disclosed methods are also useful in treatingnon-solid cancers. Exemplary solid tumors include malignancies (e.g.,sarcomas, adenocarcinomas, and carcinomas) of the various organ systems,such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon),and genitourinary (e.g., renal, urothelial, or testicular tumors)tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas includecolorectal cancers, renal-cell carcinoma, liver cancer, non-small cellcarcinoma of the lung, and cancer of the small intestine.

Other exemplary cancers include: Acute Lymphoblastic Leukemia, Adult;Acute Lymphoblastic Leukemia, Childhood; Acute Myeloid Leukemia, Adult;Adrenocortical Carcinoma; Adrenocortical Carcinoma, Childhood;AIDS-Related Lymphoma; AIDS-Related Malignancies; Anal Cancer;Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; BileDuct Cancer, Extrahepatic; Bladder Cancer; Bladder Cancer, Childhood;Bone Cancer, Osteosarcoma/Malignant Fibrous Histiocytoma; Brain StemGlioma, Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem Glioma,Childhood; Brain Tumor, Cerebellar Astrocytoma, Childhood; Brain Tumor,Cerebral Astrocytoma/Malignant Glioma, Childhood; Brain Tumor,Ependymoma, Childhood; Brain Tumor, Medulloblastoma, Childhood; BrainTumor, Supratentorial Primitive Neuroectodermal Tumors, Childhood; BrainTumor, Visual Pathway and Hypothalamic Glioma, Childhood; Brain Tumor,Childhood (Other); Breast Cancer; Breast Cancer and Pregnancy; BreastCancer, Childhood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids,Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor,Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, Islet Cell;Carcinoma of Unknown Primaiy; Central Nervous System Lymphoma, Primary;Cerebellar Astrocytoma, Childhood; Cerebral Astrocytoma/MalignantGlioma, Childhood; Cervical Cancer; Childhood Cancers; ChronicLymphocytic Leukemia; Chronic Myelogenous Leukemia; ChronicMyeloproliferative Disorders; Clear Cell Sarcoma of Tendon Sheaths;Colon Cancer; Colorectal Cancer, Childhood; Cutaneous T-CeIl Lymphoma;Endometrial Cancer; Ependymoma, Childhood; Epithelial Cancer, Ovarian;Esophageal Cancer; Esophageal Cancer, Childhood; Ewing's Family ofTumors; Extracranial Germ Cell Tumor, Childhood; Extragonadal Germ CellTumor; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma;Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach)Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointestinal CarcinoidTumor; Germ Cell Tumor, Extracranial, Childhood; Germ Cell Tumor,Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor;Glioma, Childhood Brain Stem; Glioma, Childhood Visual Pathway andHypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular(Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer,Childhood (Primary); Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma,Childhood; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer;Hypothalamic and Visual Pathway Glioma, Childhood; Intraocular Melanoma;Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; KidneyCancer; Laryngeal Cancer; Laryngeal Cancer, Childhood; Leukemia, AcuteLymphoblastic, Adult; Leukemia, Acute Lymphoblastic, Childhood;Leukemia, Acute Myeloid, Adult; Leukemia, Acute Myeloid, Childhood;Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous; Leukemia,Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary);Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; LungCancer, Small Cell; Lymphoblastic Leukemia, Adult Acute; LymphoblasticLeukemia, Childhood Acute; Lymphocytic Leukemia, Chronic; Lymphoma,AIDS-Related; Lymphoma, Central Nervous System (Primary); Lymphoma,Cutaneous T-CeIl; Lymphoma, Hodgkin's, Adult; Lymphoma, Hodgkin's,Childhood; Lymphoma, Hodgkin's During Pregnancy; Lymphoma,Non-Hodgkin's, Adult; Lymphoma, Non-Hodgkin's, Childhood; Lymphoma,Non-Hodgkin's During Pregnancy; Lymphoma, Primary Central NervousSystem; Macroglobulinemia, Waldenstrom's; Male Breast Cancer; MalignantMesothelioma, Adult; Malignant Mesothelioma, Childhood; MalignantThymoma; Medulloblastoma, Childhood; Melanoma; Melanoma, Intraocular;Merkel Cell Carcinoma; Mesothelioma, Malignant; Metastatic Squamous NeckCancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome,Childhood; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides;Myelodysplastic Syndromes; Myelogenous Leukemia, Chronic; MyeloidLeukemia, Childhood Acute; Myeloma, Multiple; MyeloproliferativeDisorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer;Nasopharyngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuroblastoma;Non-Hodgkin's Lymphoma, Adult; Non-Hodgkin's Lymphoma, Childhood;Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer;Oral Cancer, Childhood; Oral Cavity and Lip Cancer; OropharyngealCancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; OvarianCancer, Childhood; Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor;Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; PancreaticCancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal Sinus andNasal Cavity Cancer; Parathyroid Cancer; Penile Cancer;Pheochromocytoma; Pineal and Supratentorial Primitive NeuroectodermalTumors, Childhood; Pituitary Tumor; Plasma Cell Neoplasm/MultipleMyeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;Primary Central Nervous System Lymphoma; Primary Liver Cancer, Adult;Primary Liver Cancer, Childhood; Prostate Cancer; Rectal Cancer; RenalCell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Pelvis andUreter, Transitional Cell Cancer; Retinoblastoma; Rhabdomyosarcoma,Childhood; Salivary Gland Cancer; Salivary Gland Cancer, Childhood;Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma(Osteosarcoma)/Malignant Fibrous Histiocytoma of Bone; Sarcoma,Rhabdomyosarcoma, Childhood; Sarcoma, Soft Tissue, Adult; Sarcoma, SoftTissue, Childhood; Sezary Syndrome; Skin Cancer; Skin Cancer, Childhood;Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; Small Cell LungCancer; Small Intestine Cancer; Soft Tissue Sarcoma, Adult; Soft TissueSarcoma, Childhood; Squamous Neck Cancer with Occult Primary,Metastatic; Stomach (Gastric) Cancer; Stomach (Gastric) Cancer,Childhood; Supratentorial Primitive Neuroectodermal Tumors, Childhood;T-Cell Lymphoma, Cutaneous; Testicular Cancer; Thymoma, Childhood;Thymoma, Malignant; Thyroid Cancer; Thyroid Cancer, Childhood;Transitional Cell Cancer of the Renal Pelvis and Ureter; TrophoblasticTumor, Gestational; Unknown Primary Site, Cancer of, Childhood; UnusualCancers of Childhood; Ureter and Renal Pelvis, Transitional Cell Cancer;Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Visual Pathway andHypothalamic Glioma, Childhood; Vulvar Cancer; Waldenstrom's Macroglobulinemia; and Wilms' Tumor. Metastases of the aforementioned cancerscan also be treated or prevented in accordance with the methodsdescribed herein.

Cancer Combination Therapies

In some embodiments, a compound described herein is administeredtogether with one or more additional cancer treatments. Exemplary cancertreatments include, for example: chemotherapy, targeted therapies suchas antibody therapies, immunotherapy, and hormonal therapy. Examples ofeach of these treatments are provided below.

Chemotherapy

In some embodiments, a compound described herein is administered withone or morechemotherapies. Chemotherapy is the treatment of cancer withdrugs that can destroy cancer cells. “Chemotherapy” usually refers tocytotoxic drugs which affect rapidly dividing cells in general, incontrast with targeted therapy. Chemotherapy drugs interfere with celldivision in various possible ways, e.g., with the duplication of DNA orthe separation of newly formed chromosomes. Most forms of chemotherapytarget all rapidly dividing cells and are not specific for cancer cells,although some degree of specificity may come from the inability of manycancer cells to repair DNA damage, while normal cells generally can.

Examples of chemotherapeutic agents used in cancer therapy include, forexample, antimetabolites (e.g., folic acid, purine, and pyrimidinederivatives) and alkylating agents (e.g., nitrogen mustards,nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes,aziridines, spindle poison, cytotoxic agents, toposimerase inhibitorsand others). Exemplary agents include Aclarubicin, Actinomycin,Alitretinon, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan,Belotecan, Bexarotene, endamustine, Bleomycin, Bortezomib, Busulfan,Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur,Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin,Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine,Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine,Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin,Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide,Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine,Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide,Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomaldoxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone,Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate,Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin,Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel,Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin,Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,Semustine, Sitimagene ceradenovec, Satraplatin, Streptozocin,Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurin, Tioguanine,Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine,Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin,Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine,Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxicagents described herein.

Because some drugs work better together than alone, two or more drugsare often given at the same time. Often, two or more chemotherapy agentsare used as combination chemotherapy.

In some embodiments, the chemotherapy agents (including combinationchemotherapy) can be used in combination with a compound describedherein.

Targeted Therapy

In some embodiments, a compound described herein is administered withone or more targeted therapies. Targeted therapy constitutes the use ofagents specific for the deregulated proteins of cancer cells. Smallmolecule targeted therapy drugs are generally inhibitors of enzymaticdomains on mutated, overexpressed, or otherwise critical proteins withinthe cancer cell. Prominent examples are the tyrosine kinase inhibitorssuch as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib,gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib,Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitorssuch as Alvocidib and Seliciclib. Monoclonal antibody therapy is anotherstrategy in which the therapeutic agent is an antibody whichspecifically binds to a protein on the surface of the cancer cells.Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®)typically used in breast cancer, and the anti-CD20 antibody rituximaband Tositumomab typically used in a variety of B-cell malignancies.Other exemplary anbibodies include Cetuximab, Panitumumab, Trastuzumab,Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusionproteins include Aflibercept and Denileukin diftitox. In someembodiments, the targeted therapy can be used in combination with acompound described herein.

Targeted therapy can also involve small peptides as “homing devices”which can bind to cell surface receptors or affected extracellularmatrix surrounding the tumor. Radionuclides which are attached to thesepeptides (e.g., RGDs) eventually kill the cancer cell if the nuclidedecays in the vicinity of the cell. An example of such therapy includesBEXXAR®.

Immunotherapy

In some embodiments, a compound described herein is administered withone or more immunotherapies. Cancer immunotherapy refers to a diverseset of therapeutic strategies designed to induce the patient's ownimmune system to fight the tumor. Contemporary methods for generating animmune response against tumors include intravesicular BCG immunotherapyfor superficial bladder cancer, and use of interferons and othercytokines to induce an immune response in renal cell carcinoma andmelanoma patients.

Allogeneic hematopoietic stem cell transplantation can be considered aform of immunotherapy, since the donor's immune cells will often attackthe tumor in a graft-versus-tumor effect. In some embodiments, theimmunotherapy agents can be used in combination with a compounddescribed herein.

Hormonal Therapy

In some embodiments, a compound described herein is administered withone or more hormonal therapies. The growth of some cancers can beinhibited by providing or blocking certain hormones. Common examples ofhormone-sensitive tumors include certain types of breast and prostatecancers. Removing or blocking estrogen or testosterone is often animportant additional treatment. In certain cancers, administration ofhormone agonists, such as progestogens may be therapeuticallybeneficial. In some embodiments, the hormonal therapy agents can be usedin combination with a compound described herein.

Obesity and Fat Disorders

A compound or composition described herein can be used to treat orprevent obesity, e.g., in a human subject, e.g. a child or adultsubject. “Obesity” refers to a condition in which a subject has a bodymass index of greater than or equal to 30. Many compounds describedherein can be used to treat or prevent an over-weight condition.“Over-weight” refers to a condition in which a subject has a body massindex of greater or equal to 25.0. The body mass index (BMI) and otherdefinitions are according to the “NIH Clinical Guidelines on theIdentification and Evaluation, and Treatment of Overweight and Obesityin Adults” (1998). Treatment with the compound may be in an amounteffective to alter the weight of the subject, e.g., by at least 2, 5, 7,10, 12, 15, 20, 25, 30, 25, 40, 45, 50, or 55%. Treatment with acompound may be in an amount effective to reduce the body mass index ofthe subject, e.g., to less than 30, 28, 27, 25, 22, 20, or 18. Thecompounds can be used to treat or prevent aberrant or inappropriateweight gain, metabolic rate, or fat deposition, e.g., anorexia, bulimia,obesity, diabetes, or hyperlipidemia (e.g., elevated triglyceridesand/or elevated cholesterol), as well as disorders of fat or lipidmetabolism.

A compound or composition described herein can be administered to treatobesity associated with Prader-Willi Syndrome (PWS). PWS is a geneticdisorder associated with obesity (e.g., morbid obesity).

A compound or composition described herein can be used to reduce bodyfat, prevent increased body fat, reduce cholesterol (e.g., totalcholesterol and/or ratios of total cholesterol to HDL cholesterol),and/or reduce appetite in individuals having PWS associated obesity,and/or reduce comorbidities such as diabetes, cardiovascular disease,and stroke.

Compositions and Routes of Administration

The compositions delineated herein include the compounds delineatedherein (e.g., a compound described herein), as well as additionaltherapeutic agents if present, in amounts effective for achieving amodulation of disease or disease symptoms, including those describedherein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound provided herewith, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions provided herewith include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-a-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-P-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions provided herewith may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions provided herewith may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agentswhich are commonly used in the formulation of pharmaceuticallyacceptable dosage forms such as emulsions and or suspensions. Othercommonly used surfactants such as Tweens or Spans and/or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions provided herewith may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions provided herewith may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound providedherewith with a suitable non-irritating excipient which is solid at roomtemperature but liquid at the rectal temperature and therefore will meltin the rectum to release the active components. Such materials include,but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical compositions providedherewith is useful when the desired treatment involves areas or organsreadily accessible by topical application. For application topically tothe skin, the pharmaceutical composition should be formulated with asuitable ointment containing the active components suspended ordissolved in a carrier. Carriers for topical administration of thecompounds provided herewith include, but are not limited to, mineraloil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions provided herewith may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded.

The pharmaceutical compositions provided herewith may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

When the compositions provided herewith comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds provided herewith. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds providedherewith in a single composition.

The compounds described herein can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect.

Typically, the pharmaceutical compositions provided herewith will beadministered from about 1 to about 6 times per day or alternatively, asa continuous infusion. Such administration can be used as a chronic oracute therapy. The amount of active ingredient that may be combined withthe carrier materials to produce a single dosage form will varydepending upon the host treated and the particular mode ofadministration. A typical preparation will contain from about 5% toabout 95% active compound (w/w). Alternatively, such preparationscontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination provided herewith may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Patient Selection and Monitoring

The compounds described herein can modulate PKM2. Accordingly, a patientand/or subject can be selected for treatment using a compound describedherein by first evaluating the patient and/or subject to determinewhether the subject is in need of modulation of PKM2, and if the subjectis determined to be in need of modulation of PKM2, then administering tothe subject a compound described herein.

A subject can be evaluated as being in need of modulation of PKM2 usingmethods known in the art, e.g., by measuring the presence and/oractivity of PKM2 in the patient. In some embodiments, the activityand/or level of PKM2 is evaluated in the cancer.

A patient receiving a compound described herein can be monitored, forexample, for improvement in the condition and/or adverse effects.Improvement of a patient's condition can be evaluated, for example, bymonitoring the growth, absence of growth, or regression of the cancer(e.g., a tumor). In some embodiments, the patient is evaluated using aradiological assay or evaluation of hemolytic parameters.

EXAMPLES Example 1. PKM2 Assay Procedure

-   -   PKM2 stock enzyme solution was diluted in Reaction Buffer    -   2 μL of compound was added into each well first, and then 180 μL        of the Reaction Mix was added.    -   Reaction mixture with compound (without ADP) were incubated for        30 minutes at 4° C.    -   Plates were re-equilibrated to room temperature prior to adding        20 L ADP to initiate the reaction.    -   Reaction progress was measured as changes in absorbance at 340        nm wavelength at room temperature (25° C.)        Reaction Mix: PKM2 (50 ng/well), ADP (0.7 mM), PEP (0.15 mM),        NADH (180 μM), LDH (2 units) in Reaction Buffer

Reaction Buffer: 100 mM KCl, 50 mM Tris pH 7.5, 5 mM MgCl2, 1 mM DTT,0.03% BSA. Example 2: Compounds and Their Preparation

General procedure for Compound 1: To a solution of 4-bromo phenol (5.0,0.0289 moles, 1 eq) in DMF (50 mL), potassium carbonate (9.970 g, 0.0722moles, 2.5 eq) was added followed by the addition of ethyl iodide (4.70ml, 0.0578 moles, 2 eq) and stirred for overnight. The progress of thereaction was monitored by TLC. After completion of starting material,the reaction mixture was quenched with water (25 mL) and extracted withethylacetate (2×50 mL). The combined organic layers were washed withbrine (40 ml) solution. Ethylacetate layer was dried over Na₂SO₄ andconcentrated under reduced pressure. The crude product was purified bycolumn chromatography (9:1, ethyl acetate/hexane) to obtain compound 1(5.0 g, 86.2%). MS (201.06) 202.1 (M+1).

General procedure for Compound 2: Compound 1 was taken in a two neckedflask (2.00 g, 0.0099 moles, 1 eq). Chlorosulfonic acid (25 mL, 0.358moles, 36 eq) was added slowly over a period of 10 min at −10° C. Theresulting mixture was stirred at the same temperature for 10 min. Aftercompletion of the starting material, the reaction mixture was pouredinto ice cold water (100 mL) and extracted with ethyl acetate. Theorganic layer was washed with H₂O, dried over Na₂SO₄ and concentratedunder reduced pressure. The desired product 2 was obtained by columnpurification (60-120 mesh silica gel, 5% ethyl acetate-hexane) as asolid (3 g, 43.3%).

General procedure for Compound 3: To a solution of ethyl-4-aminobenzoate(300 mg, 1.81 mmole, 1 eq) in 1:1 mixture of DCM/pyridine (5 mL/5 mL)was added a solution of 5-bromo-2-ethoxybenzene-1-sulfonyl chloride(compound 2, 654 mg, 2.17 mmole, 1.2 eq) in DCM (5 mL/5 mL) at 0° C. Thereaction mixture was then allowed to stir at room temperature forovernight.

After completion of the reaction, the reaction mixture was diluted withDCM and washed with water, dried over sodium sulphate and concentratedunder reduced pressure. The crude product was then washed with diethylether followed by n-hexane and dried to yield compound 3 as an off whitesolid (0.600 g, 77%).

¹H NMR (200 MHz, DMSO-d₆) 1.30 (t, 3H), 1.58 (t, 3H), 4.20-4.40 (m, 4H),6.82 (d, 1H), 7.10-7.20 (m, 2H), 7.56-7.60 (dd, 1H), 7.90-8.00 (m, 3H).

General procedure for Compound 4: Ethyl4-(5-bromo-2-ethoxyphenylslulfonamido) benzoate (compound 3, 600 mg,0.0014 moles, 1 eq) was taken in THF-H₂O (1:1, 30 mL/30 mL). LiOH.H₂O(0.293 g, 0.007 moles, 5 eq) was then added to the above reactionmixture and stirred at reflux for overnight. After completion of thestarting material, the solvent was removed under reduced pressure toobtain the crude product. The crude product was washed with ethylacetate. The aqueous layer was acidified with citric acid (_(p)H=4) andextracted again with ethyl acetate (2×25 mL). The combined organic layerwas dried over Na₂SO₄ and concentrated under reduced pressure. Theresultant acid was further washed with hexane to get pure compound 4(0.500 g, 89%).

MS (400.24) 397.9 (M-2 peak, negative mode); ¹H NMR (200 MHz, DMSO-d₆)1.20 (t, 3H), 4.18 (q, 2H), 7.10 (d, 1H), 7.10-7.20 (d, 3H), 7.60-8.0(m, 4H), 10.6 (s, 1H), 12.6 (bs, 1H).

General procedure for Compound 7: To a solution of4-(5-bromo-2-ethoxyphenylsulfonamido)benzoic acid (compound 4, 0.300 g,0.00074 moles, 1 eq) in DMF (25 mL), EDCI (0.157 g, 0.00082 moles, 1.1eq), HOBt (0.126 g, 0.00082 moles, 1.1 eq) and DIPEA (0.48 mL, 0.0026moles, 3.5 eq) were added at 0° C. and stirred for 15 minutes. Asolution of 1-2-(methoxyphenyl) piperazine (Compound 6, 0.171 g, 0.00074moles, 1 eq) was then added at 0° C. and then the resulting mixture wasallowed to stir at room temperature for overnight. After completion ofthe reaction, water (30 mL) was added and extracted with ethyl acetate(2×30 mL). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The crude product was dissolvedin EtOAc and to this pentane was added to yield compound 7 as a whitesolid which was filtered and dried (200 mg, 46.5% yield).

¹H NMR (500 MHz, DMSO-d₆) 1.30 (t, 3H), 2.80-3.0 (bs, 4H), 3.30-3.60(bm, 4H), 3.78 (s, 3H), 4.20 (q, 2H), 6.80-7.00 (m, 4H), 7.10-7.20 (m,3H), 7.30-7.34 (d, 2H), 7.70-7.75 (dd, 1H), 7.80 (d, 1H), 10.35 (s, 1H);MS 574.0; MS base peak at 574.0; HPLC purity 97.80%.

Synthesis of Compound 6:

General procedure for Compound 5: In a two neck round bottom flask,tert-butyl piperazine-1-carboxylate (4.97 g, 0.0267 moles, 1 eq),2-bromo anisole (5.0 g, 0.0267 moles, 1 eq) and CS₂CO₃ (21.7 g, 0.0668moles, 2.5 eq) were charged in degassed 1,4-dioxane (100 mL) under N₂atmosphere. BINAP (1.49 g, 0.00240 moles, 0.09 eq) and Pd (OAc)₂ (0.96g, 0.00042 moles, 0.016 eq) were then added to the reaction mixtureunder N₂ atmosphere and stirred at 80° C. for overnight. The progress ofthe reaction was monitored by TLC. After completion of the startingmaterial, the excess of solvent was distilled off under reduced pressureand the residue was diluted with water and extracted with ethyl acetate.The organic layer was separated, dried over Na₂SO₄ and concentratedunder reduced pressure. The crude product was purified by columnchromatography (silica gel 60-120, 5-6%, ethyl acetate/hexane) to yieldthe desired product 5 as viscous oil (2.8 g, 36%).

¹H NMR (500 MHz, CDCl₃): 1.42 (s, 9H), 3.0 (m, 4H), 3.60 (m, 4H), 3.84(s, 3H), 6.80-7.00 (m, 4H); MS 293.1 (M+1 peak).

General procedure for Compound 6: In a two neck RB flask,tert-butyl-4-(2-methoxyphenyl) piperazine-1-carboxylate (compound 5,0.600 g, 0.00205 moles, 1 eq) was treated with ether-HCl (10 mL). Theresulting mixture was stirred for overnight. After completion of thestarting material as indicated by TLC, ether was removed under reducedpressure and a solid material was obtained. The solid material waswashed with ethyl acetate and dried to obtain the amine compound 6 as awhite solid (0.425 g, 90.08%).

The following analogs were prepared utilizing the above procedure withvarious sulfonyl chlorides in place of compound 2.

5-Chloro-2-methoxy-N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(8)

Compound 8 was prepared from commercially available2-Methoxy-5-chlorobenzenesulfonyl chloride as shown in Scheme 2.

¹H NMR (500 MHz, DMSO-d₆) 2.8-3.0 (bm, 4H), 3.40-3.78 (m, 4H), 3.80 (s,3H), 3.84 (s, 3H), 6.80-7.00 (m, 4H), 7.12 (d, 2H), 7.21 (d, 1H), 7.30(d, 2H), 7.65 (dd, 1H), 7.74 (d, 1H); MS base peak at m/z 516; HPLCpurity: 94.33%

5-Bromo-2-methoxy-N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(9)

The corresponding sulfonyl chloride was prepared from 4-bromophenol.O-Methylation of 4-bromophenol followed by chlorosulfonic acid reactiongave 2-methoxy-5-bromobenzenesulfonyl chloride which was utilized toproduce compound 9 as provided in Scheme 2.

¹H NMR (500 MHz, DMSO-d₆) 2.90-3.00 (bm, 4H), 3.40-3.78 (m, 4H), 3.80(s, 3H), 3.84 (s, 3H), 6.80-7.00 (m, 4H), 7.10-7.18 (m, 3H), 7.30 (d,2H), 7.70 (dd, 1H), 7.74 (d, 1H); MS base peak at 562.0; HPLC purity:94.36%

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)naphthalene-2-sulfonamide(10)

Commercially available naphthalene-2-sulfonyl chloride was utilized inplace of compound 2 used to provide 10.

¹H NMR (500 MHz, DMSO-d₆) 2.80-3.00 (bm, 4H), 3.40-3.78 (m, 4H), 3.80(s, 3H), 6.80-7.00 (m, 4H), 7.10-7.30 (m, 4H), 7.60-7.80 (m, 3H),8.00-8.20 (m, 3H), 8.50 (s, 1H), 10.7 (s, 1H); MS base peak at 504.2;HPLC purity: 93.65% (UPLC)

5-Chloro-2-ethoxy-N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(11)

The corresponding sulfonyl chloride was prepared from 4-chlorophenol.O-Ethylation of 4-chlorophenol followed by a chlorosulfonic acidreaction under the appropriate conditions provided2-ethoxy-5-chlorobenzenesulfonyl chloride which was utilized to preparecompound 11 as shown in Scheme 2.

¹H NMR (500 MHz, DMSO-d₆) 1.30 (t, 3H), 2.80-3.0 (bs, 4H), 3.40-3.78(bm, 4H), 3.80 (s, 3H), 4.20 (q, 2H), 6.80-7.00 (m, 4H), 7.16 (d, 2H),7.20 (d, 1H), 7.38 (d, 2H), 7.60 (d, 1H), 7.80 (s, 1H), 10.20 (s, 1H);MS base peak at 530.1; HPLC purity 97.48%

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(12)

Compound 12 was prepared following Scheme 2 using benzenesulfonylchloride. ¹H NMR (500 MHz, DMSO-d₆) 2.90-3.00 (bs, 4H), 3.40-3.78 (bm,4H), 3.80 (s, 3H), 6.84-6.98 (m, 4H), 7.15 (d, 2H), 7.30 (d, 2H),7.56-7.64 (m, 3H), 7.80 (d, 2H), 10.6 (s, 1H); MS base peak at 452.6;HPLC purity 96.90%.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)naphthalene-1-sulfonamide(13)

Compound 13 was prepared following Scheme 2 using commercially availablenaphthalene-1-sulfonyl chloride.

¹H NMR (500 MHz, DMSO-d₆) 2.90-3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80(s, 3H), 6.84-6.98 (m, 4H), 7.10 (d, 2H), 7.24 (d, 2H), 7.62-7.78 (m,3H), 8.08 (d, 1H), 8.23 (d, 1H), 8.28 (d, 1H), 8.72 (d, 1H), 10.98 (s,1H); MS base peak at 502.1; HPLC purity 96.59%.

2,6-Difluoro-N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(14)

Compound 14 was prepared following Scheme 2 using commercially available2,6-difluorobenzenesulfonyl chloride.

¹H NMR (500 MHz, DMSO-d₆) 2.90-3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80(s, 3H), 6.84-7.00 (m, 4H), 7.20 (d, 2H), 7.30 (t, 2H), 7.38 (d, 2H),7.68-7.74 (m, 1H), 11.2 (s, 1H); MS base peak at 488.1; HPLC purity97.16%.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(15)

Compound 15 was prepared following Scheme 2 using commercially availablequinoline-8-sulfonyl chloride.

¹H NMR (500 MHz, DMSO-d₆) 2.90-3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80(s, 3H), 6.82 (d, 2H), 6.90-7.00 (m, 2H), 7.15-7.20 (2 doublets, 4H),7.70-7.78 (m, 2H), 8.24 (d, 1H), 8.40 (d, 1H), 8.50 (d, 1H), 9.15 (bs,1H), 10.42 (s, 1H); MS base peak at 503.2; HPLC purity 97.11%.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzo[d]thiazole-5-sulfonamide(17)

Compound 17 was prepared from commercially availablebenzthiazole-6-sulfonyl chloride following the Scheme 2 protocol.

¹H NMR (500 MHz, DMSO-d₆) 2.90-3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80(s, 3H), 6.82-7.00 (m, 4H), 7.20 (d, 2H), 7.38 (d, 2H), 7.90 (d, 1H),8.22 (d, 1H), 8.78 (s, 1H), 9.60 (s, 1H), 10.70 (s, 1H); MS base peak at509.1; HPLC purity 97.29%

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)-3,5-dimethylbenzene-sulfonamide(18)

Compound 18 was prepared from commercially available3,5-dimethylbenzenesulfonyl chloride following the protocol provided inScheme 2.

¹H NMR (500 MHz, DMSO-d₆) 2.35 (s, 6H), 2.80-2.90 (m, 4H), 3.42-3.78(bm, 4H), 3.80 (s, 3H), 6.88 (bs, 2H), 6.92-7.00 (m, 2H), 7.15 (d, 2H),7.26 (s, 1H), 7.33 (d, 2H), 7.42 (s, 2H), 10.5 (s, 1H); MS base peak at480.3; HPLC purity 98.56%.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide-(19)

Compound 19 was prepared from commercially available2,3-dihydrobenzodioxo-6-sulfonyl chloride following the protocolprovided in Scheme 2.

¹H NMR (500 MHz, DMSO-d₆) 2.80-3.00 (m, 4H), 3.42-3.78 (bm, 4H), 3.80(s, 3H), 4.25 (m, 4H), 6.86-6.88 (m, 2H), 6.92-6.98 (m, 2H), 7.00 (d,1H), 7.15 (d, 2H), 7.24 (s, 1H), 7.26-7.30 (dd, 1H), 7.34 (d, 2H), 10.5(s, 1H); MS base peak at 510.3; HPLC purity 97.02%.

5-Chloro-2-methoxy-N-(4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)phenyl)benzene-sulfonamide(19a)

Compound 19a was prepared according to Scheme 2. N-boc-homopiperazinewas utilized in place of N-Boc-piperazine to prepare theN-2-methoxyphenyl-homopiperazine intermediate through a Buchwaldreaction as provided in Scheme 3.

¹H NMR (500 MHz, DMSO-d₆) 1.70 (s, 1H), 1.90 (s, 1H), 3.10-3.40 (m, 9H),3.60-3.80 (m, 2H), 3.82 (s, 3H), 6.70-6.82 (m, 4H), 6.96-7.30 (m, 5H),7.66 (t, 1H), 7.74 (s, 1H), 10.40 (d, 1H); MS base peak at 530.1; HPLCpurity 95.89%.

N-(4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(19b)

¹H NMR (500 MHz, DMSO-d₆) 1.70 (s, 1H), 1.90 (s, 1H), 3.10-3.40 (m, 8H),3.58-3.80 (m, 3H), 6.58 (d, 1H), 6.70-7.20 (m, 7H), 7.80 (m, 2H), 8.30(t, 1H), 8.40 (d, 1H), 8.56 (t, 1H), 9.18 (s, 1H), 10.40 (d, 1H); MSbase peak at 517.2; HPLC purity 97.60%.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)2-methylbenzo[d]thiazole-4-sulfonamide(35)

2-methylbenzothiazole-4-sulfonyl chloride was prepared according to U.S.Pat. No. 4,643,759. Compound 35 was prepared following the generalprocedure described in Scheme 2.

¹H NMR (500 MHz, DMSO-d₆) 2.80 (s, 3H), 3.00 (bs, 4H), 3.40-3.78 (m,4H), 3.80 (s, 3H), 6.90 (s, 2H), 6.90-7.0 (m, 2H), 7.18 (d, 2H), 7.30(d, 2H), 7.82 (d, 1H), 8.04 (d, 1H), 8.60 (s, 1H), 10.6 (1H); MS basepeak at 523.4; LCMS purity 97.38%

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)thiophene-2-sulfonamide(36)

Compound 36 was prepared from commercially availablethiophene-2-sulfonyl chloride according to the general proceduredescribed in Scheme 2.

¹H NMR (500 MHz, DMSO-d₆) 2.90-3.00 (bs, 4H), 3.30-3.78 (bm, 4H), 3.80(s, 3H), 6.80-6.90 (m, 2H), 6.90-7.0 (m, 2H), 7.18 (d, 1H), 7.20 (d,2H), 7.40 (d, 2H), 7.60 (s, 1H), 7.94 (d, 1H), 10.70 (s, 1H); MS basepeak at 458.2; HPLC purity 95.02%.

Synthesis of Phenyl Analogues:

Procedure for the synthesis of compound 20: To a solution of2-methoxy-5-chlorobenzenesulfonyl chloride (878 mg, 0.00362 moles, 1.5eq) in dichloromethane was added a solution of ethyl 4-aminobenzoate(400 mg, 0.00242 moles, 1 eq) in 1:1 ratio of pyridine and DCM (5 mL/5mL) under nitrogen atmosphere at 0° C. The reaction mixture was stirredat room temperature overnight. The progress of the reaction wasmonitored by TLC. Upon completion, the reaction mixture was diluted withDCM, washed twice with water, and dried with anhydrous sodium sulphate.The organic layer was concentrated, dried, washed with ether followed byn-hexane and dried to provide 20 as an off-white solid (0.8 g, 89%yield).

¹H NMR (500 MHz, CDCl₃) 1.34 (t, 3H), 4.0 (s, 3H), 4.22-4.32 (q, 2H),6.90 (d, 1H), 7.16 (d, 2H), 7.20 (s, 1H), 7.84 (s, 1H), 7.92 (d, 2H).

Procedure for the synthesis of compound 21: LiOH (226 mg, 0.0049 moles,4 eq) was added to a stirred solution of compound 20 (500 mg, 0.0013moles, 1 eq) in THF-H₂O mixture (1:1 ration, 30 ml/30 ml) and heated atreflux overnight. The progress of the reaction was monitored by TLC.Upon completion, the reaction mixture was acidified with citric acid topH 4 and extracted with ethyl acetate. The ethyl acetate layer waswashed with water, dried over sodium sulfate and distilled. Theresulting solid 21 was dried and used without purification in thefollowing step (400 mg, 87% yield).

¹H NMR (500 MHz, DMSO-d6) 3.82 (s, 3H), 7.10-7.22 (m, 3H), 7.62 (d, 1H),7.88-7.92 (m, 3H), 10.64 (s, 1H), 12.70 (s, 1H).

Procedure for the synthesis of compound 22: The synthesis of compound 22was carried out following a procedure similar to compound 5 utilizingbromobenzene in place of 2-bromoanisole. MS 263 (M+1 peak).

Procedure for the synthesis of compound 23: Compound 22 (500 mg) wasdissolved in 30 ml of ether/HCl and stirred for 2 hrs at roomtemperature under a nitrogen atmosphere. The reaction mixture wasdistilled under reduced pressure to remove ether, washed with pentaneand dried over sodium sulfate to obtain compound 23 (300 mg, 97% yield).

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (m, 4H), 3.40-3.42 (m, 4H), 6.80 (t,1H), 7.00 (d, 2H), 7.22 (t, 2H), 9.0 (bs, 1H), 9.40 (bs, 2H).

Procedure for the synthesis of compound 24: To a stirred solution ofcompound 21 (100 mg, 0.00029 moles, 1 eq) in DMF (10 mL) was added EDCI(62 mg, 0.00032 moles, 1.1 eq), HOBt (50 mg, 0.00032 moles, 1.1 eq) andDIPEA (0.16 ml, 0.00088 moles, 3 eq) at 0° C. under a nitrogenatmosphere. The reaction mixture was stirred for 5 minutes at 0° C. andthen at room temperature for 30 minutes. A solution of compound 23 (59mg, 0.00029 moles, 1 eq) dissolved in DMF and half equivalent of DIPEAwas added slowly to the above reaction mixture at 0° C. and allowed tostir at room temperature overnight. The reaction was monitored by TLC.Upon completion, the reaction mixture was washed with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated under vacuum. The crude product was purified bycrystallization with an ethyl acetate/hexane solvent mixture to obtaincompound 24 in 24.6% yield (35 mg).

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (bs, 4H), 3.40-3.78 (bm, 4H), 3.82(s, 3H), 6.80 (t, 1H), 6.90 (d, 2H), 7.14 (d, 2H), 7.20 (t, 3H), 7.30(d, 2H), 7.62-7.66 (dd, 1H), 7.74 (d, 1H), 10.40 (s, 1H); MS base peakat 486.0; HPLC purity 97.34%.

**Compounds 25 to 30 were prepared following a protocol similar to thatdescribed in Scheme 4.

N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)benzenesulfonamide (25)

Compound 25 was prepared using benzenesulfonyl chloride following aprotocol similar to that shown in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (bs, 4H), 3.40-3.78 (bm, 4H), 6.80(t, 1H), 6.92 (d, 2H), 7.10-7.35 (m, 6H), 7.50-7.70 (m, 3H), 7.80 (d,2H), 10.60 (s, 1H); MS base peak at 422.0; HPLC purity 97.92%.

4-Fluro-N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)benzenesulfonamide(26)

Compound 26 was made using 4-fluorobenzenesulfonyl chloride following asimilar procedure as provided in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (bs, 4H), 3.40-3.80 (bm, 4H), 6.80(t, 1H), 6.94 (d, 2H), 7.14 (d, 2H), 7.20 (t, 2H), 7.32 (d, 2H), 7.35(t, 2H), 7.80-7.90 (m, 2H), 10.6 (s, 1H); MS base peak at 440.1; HPLCpurity 96.72%.

3-Chloro-N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)benzenesulfonamide(27)

Compound 27 was prepared using ommercial 3-chlorobenzenesulfonylchloride following a similar procedure as provided in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (bs, 4H), 3.40-3.80 (bm, 4H), 6.80(t, 1H), 7.00 (d, 2H), 7.18-7.22 (m, 4H), 7.38 (d, 2H), 7.60 (t, 1H),7.70-7.80 (m, 3H), 10.6 (s, 1H); MS base peak at 456.2; HPLC purity97.25%.

3-Methoxy-N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)benzenesulfonamide(28)

Compound 28 was prepared using 3-methoxybenzenesulfonyl chlorideaccording to the general procedure provided in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80(s, 3H), 6.80 (t, 1H), 6.95 (d, 2H), 7.14-7.24 (m, 5H), 7.28 (bs, 1H),7.32-7.40 (m, 3H), 7.50 (t, 1H), 10.6 (s, 1H); MS base peak at 452.2;HPLC purity 93.60%.

2-Chloro-N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)benzenesulfonamide(29)

Compound 29 was prepared using commercially available2-chlorobenzenesulfonyl chloride according to the general procedureprovided in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (bs, 4H), 3.40-3.78 (bm, 4H), 6.80(t, 1H), 6.95 (d, 2H), 7.16-7.38 (m, 6H), 7.58 (t, 1H), 7.64 (d, 2H),8.10 (d, 1H), 10.90 (s, 1H); MS base peak at 456.2; HPLC purity 99.21%.

N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)naphthalene-1-sulfonamide(30)

Compound 30 was prepared using commercially availablenaphthalene-1-sulfonyl chloride according to the general procedureprovided in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.10-3.20 (bs, 4H), 3.40-3.78 (bm, 4H), 6.80(t, 1H), 6.95 (d, 2H), 7.08 (d, 2H), 7.10-7.30 (m, 4H), 7.70-7.80 (m,3H), 8.10 (d, 1H), 8.20-8.30 (m, 2H), 8.76 (d, 1H), 11.0 (s, 1H); MSbase peak at 472.3; HPLC purity 99.14%.

N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide (30a)

¹H NMR (500 MHz, DMSO-d₆) 3.00-3.20 (bm, 4H), 3.30-3.70 (bs, 4H), 6.80(t, 1H), 6.90 (d, 2H), 7.10-7.22 (m, 6H), 7.70-7.80 (m, 2H), 8.30 (d,1H), 8.44 (d, 1H), 8.56 (d, 1H), 9.18 (d, 1H), 10.42 (s, 1H); MS basepeak at 473.2; HPLC purity 98.50%.

Synthesis of 4-Methoxy Phenyl Analogues

Synthesis of Compound 31:

To a solution of 4-bromoanisole (2.0 g, 0.0106 moles, 1 eq) in1,4-dioxane (30 mL), N₂ gas was purged for 30 minutes at roomtemperature followed by the addition of Cs₂CO₃ (7.64 g, 0.023 moles, 2.2eq), BINAP (598 mg, 0.00096 moles, 0.09 eq), Pd(OAc)₂ (38 mg, 0.00017moles, 0.016 eq) and tetrabutylammonium iodide (15 mg). The reactionmixture was purged with nitrogen again for another 15 minutes followedby addition of N-Boc-piperazine (2.38 g, 0.0128 moles, 1.2 eq). Thereaction mixture was heated at 80° C. overnight and monitored by TLC.The excess solvent was distilled off under reduced pressure and theresidue was diluted with water and extracted with ethyl acetate. Theorganic layer was separated, washed once again with water, dried oversodium sulfate and concentrated. The crude material was purified bycolumn chromatography using 60-120 mesh silica gel (15% Ethylacetate/hexane) to afford 1.5 g (48.3% yield) of compound 31.

Synthesis of compound 32: Compound 31 was stirred at room temperaturefor 2 hrs in 60 ml of ether/HCl. The excess of solvent was removed underreduced pressure and the resultant solid was washed with n-hexane anddried to obtain 780 mg (99.7% yield) of compound 32.

5-Chloro-2-methoxy-N-(4-(4-(4-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(33)

Compound 33 was prepared following the protocol described for compound24 in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.00 (bs, 4H), 3.40-3.70 (m, 7H), 3.80 (s,3H), 6.80-6.90 (dd, 4H), 7.14 (d, 2H), 7.22 (d, 1H), 7.30 (d, 2H),7.62-7.66 (dd, 1H), 7.74 (d, 1H), 10.4 (s, 1H); MS base peak at 557.1;HPLC purity 94.14%.

5-Fluoro-2-methoxy-N-(4-(4-(4-methoxyphenyl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(34)

Compound 34 was prepared following the general protocol provided inScheme 4 starting from 2-methoxy-4-fluorobenzenesulfonyl chloride.

¹H NMR (500 MHz, DMSO-d₆) 3.00 (bs, 4H), 3.40-3.70 (m, 7H), 3.82 (s,3H), 6.80-6.90 (dd, 4H), 7.14 (d, 2H), 7.20 (dd, 1H), 7.30 (d, 2H),7.46-7.49 (m, 1H), 7.60 (dd, 1H), 10.4 (s, 1H); MS base peak at 500.2;HPLC purity 95.48%.

Synthesis of 4-Chloro Pyrimidine Analogues

Preparation of Compound 37: 2,4-dichloropyrimidine (801 mg, 0.0053 mole,1 eq), N-Boc-piperazine (1.0 gm, 0.0053 mole, 1 eq) and sodiumbicarbonate (903 mg, 0.0107 mole, 2 eq) were dissolved in ethanol (50ml) and stirred at reflux for 1 h. Progress of the reaction wasmonitored by TLC. The excess solvent was removed, dissolved in water andextracted with DCM. The organic layer was washed with water, dried withsodium sulfate and concentrated under reduced pressure. The crudeproduct was purified on silica gel (60-120 mesh) using 15% ethylacetate-hexane to afford coupled product compound 37 (230 mg).

¹H NMR (500 MHz, CDCl₃) 1.5 (s, 9H), 3.5 (m, 4H), 3.80 (m, 4H), 6.80 (d,1H), 8.20 (d, 1H).

Preparation of Compound 38: A solution of compound 37 in 20 ml ofether/HCl was allowed to stir at room temperature under nitrogenatmosphere for 1 h. The excess solvent was distilled off under reducedpressure and the crude material was washed with n-pentane and dried toyield 180 mg of compound 38 in quantitative yield.

Preparation of Compound 39: To a stirred solution of compound 21 (109mg, 0.31 mmole, 1.0 eq) in DMF (15 mL), was added EDCI (67 mg, 0.35mmoles, 1.1 eq), HOBt (53.7 mg, 0.35, 1.1 eq) and DIPEA (2.0 eq) at 0°C. under a nitrogen atmosphere. The reaction mixture was allowed to stirat room temperature for 30 minutes. A solution of compound 38 (75 mg,0.319 mmoles, 1 eq) in 5 ml of DMF and 1.5 eq of DIPEA was added slowlyto reaction mixture at 0° C. and stirred at room temperature for 12 h.The reaction was monitored by TLC. After completion, the reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was separated, dried over sodium sulfate and concentratedunder reduced pressure. The crude product was purified on silica gelcolumn (60-120 mesh) using 2% MeOH-DCM to afford 30 mg of compound 39 in18% yield.

5-Chloro-N-(4-(4-(4-Chloropyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-2-methoxybenzenesulfonamide (39)

¹H NMR (500 MHz, DMSO-d₆) 3.35-3.60 (bs, 4H), 3.70-3.78 (bm, 4H), 3.80(s, 3H), 6.78 (d, 1H), 7.16 (d, 2H), 7.22 (d, 1H), 7.36 (d, 2H), 7.66(d, 1H), 7.80 (s, 1H), 8.18 (s, 1H), 10.50 (s, 1H); MS base peak at522.1; HPLC purity 96.50%.

N-(4-(4-(4-Chloropyrimidin-2-yl)piperazine-1-carbonyl)phenyl)-4-fluorobenzenesulfonamide (40)

Compound 40 was prepared in-part by following the protocols establishedfor the compound 38 coupling of pyrimidine as provided in Scheme 6 andsubsequently by following general procedures as described in Scheme 4starting from 4-fluorobenzenesulfonyl chloride.

¹H NMR (500 MHz, DMSO-d₆) 3.35-3.60 (bs, 4H), 3.70-3.78 (bm, 4H), 6.78(d, 1H), 7.18 (d, 2H), 7.38 (d, 2H), 7.42 (d, 2H), 7.82 (d, 2H), 8.38(d, 1H), 10.60 (s, 1H); MS base peak at 476.2; HPLC purity 97.89%.

Synthesis of 2-pyrimidine Analogues

Preparation of Compound 41: To a solution of 2-bromopyrimidine (500 mg,0.003144 moles, 1 eq) in ethanol (50 ml) was added sodium bicarbonate(528 mg, 0.0062 moles, 2 eq) followed by N-Boc-piperazine (585 mg,0.0031 moles, 1.0 eq). The reaction mixture was allowed to stir atreflux for 1 h and monitored by TLC. Upon completion, the excess solventwas removed under reduced pressure. The crude material was diluted withwater and extracted with ethyl acetate. The organic layer was dried oversodium sulphate and concentrated. The crude material was washed withhexane and dried to obtain 400 mg of compound 41 (48% yield).

Preparation of Compound 42: A solution of compound 41 (400 mg) inether/HCl (30 ml) was stirred at room temperature for 2 hrs andmonitored by TLC. After 2 hrs, the reaction mixture was concentratedunder reduced pressure to yield compound 42 (300 mg, 98% yield) whichwas subsequently washed with hexane and used without purification.

Preparation of Compound 43: To a solution of compound 21 (100 mg,0.00029 moles, 1 eq) in DMF (15 mL) was added EDCI (61.5 mg, 0.00032moles, 1.1), HOBt (49.28 mg, 0.00032 moles, 1.1 eq) and 1.5 equivalentsof DIPEA at 0° C. and stirred at room temperature for 30 minutes. Tothis, a solution of compound 42 in DMF (5 ml) and 2 eq of DIPEA wasadded at 0° C. and stirred at room temperature overnight. The reactionmixture was quenched with water and extracted with ethyl acetate. Theorganic layer was washed with water, dried over sodium sulfate andconcentrated under reduced pressure to provide the crude product. Thecrude material was purified on a silica gel (230-400 mesh) column with3% MeOH/DCM to yield compound 43 in 31.6% yield (45 mg).

5-Chloro-2-methoxy-N-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(43)

¹H NMR (500 MHz, DMSO-d₆) 3.35-3.70 (bm, 4H), 3.70-3.80 (bm, 4H), 3.82(s, 3H), 6.62 (d, 1H), 7.15 (d, 2H), 7.22 (d, 1H), 7.34 (d, 2H),7.62-7.66 (dd, 1H), 7.75 (d, 1H), 8.40 (s, 2H), 10.5 (s, 1H); MS basepeak at 488.3; HPLC purity 97.47%.

4-Chloro-N-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)benzenesulfonamide(44)

Compound 44 was prepared from 4-chlorobenzenesulfonyl chloride followingthe protocol described in Scheme 7 and utilizing the general proceduredescribed in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.35-3.70 (bm, 4H), 3.70-3.80 (bm, 4H), 6.62(t, 1H), 7.18 (d, 2H), 7.38 (d, 2H), 7.62 (d, 2H), 7.80 (d, 2H), 8.40(d, 2H), 10.62 (s, 1H); MS base peak at 458.2; HPLC purity 98.41%.

N-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(45)

Compound 45 was prepared from 4-chlorobenzenesulfonyl chloride followingthe protocol described in Scheme 7 using the general procedure providedin Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.30-3.80 (bm, 8H), 6.62 (t, 1H), 7.18 (d,2H), 7.22 (d, 2H), 7.64-7.80 (m, 2H), 8.30 (d, 1H), 8.38 (d, 2H), 8.42(d, 1H), 8.58 (d, 1H), 9.18 (d, 1H), 10.42 (s, 1H); MS base peak at475.2; HPLC purity 99.52%.

Synthesis of Pyrazine Analogues:

Preparation of Compound 46: To a solution of 2-chloropyrazine (500 mg,0.0027 moles, 1 eq) in DMF (20 ml) was added cesium carbonate (1.7 g,0.0052 moles, 2 eq) followed by N-Boc-piperazine (506.8 mg, 0.0027moles, 1.0 eq). The reaction mixture was heated at 100° C. for 12 hrsand monitored by TLC. Upon completion, the excess solvent was removedunder reduced pressure and the crude material was diluted with water andextracted with ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated. The crude material was washed, purified onsilica gel (60-120 mesh) using 30% ethylacetate-hexane to provide 400 mgof compound 46 (44.1% yield).

Preparation of Compound 47: A solution of compound 46 (250 mg) inether/HCl (30 ml) was stirred at room temperature for 1 h and monitoredby TLC. After 1 h, the reaction mixture was concentrated under reducedpressure to yield compound 47 (200 mg, 98% yield) which was washed withhexane and used without further purification.

Preparation of Compound 48: To a solution of compound 21 (100 mg,0.00029 moles, 1 eq) in DMF (15 mL) was added EDCI (61.5 mg, 0.00032moles, 1.1), HOBt (49.28 mg, 0.00032 moles, 1.1 eq) and 1.5 equivalentsof DIPEA at 0° C. and stirred at room temperature for 30 minutes. Tothis, a solution of compound 47 (58.7 mg, 0.00029 moles, 1 eq) in DMF (5ml) and 3 eq. of DIPEA was added at 0° C. and stirred at roomtemperature for 12 h. The reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with water,dried over sodium sulfate and concentrated under reduced pressure toprovide the crude product.

The crude material was subsequently purified on silica gel (60-120 mesh)with ethyl acetate to yield compound 48 in 31.6% yield (45 mg).

5-Chloro-2-methoxy-N-(4-(4-(pyrazin-2-yl)piperazine-1-carbonyl)phenyl)benzene-sulfonamide(48)

¹H NMR (500 MHz, DMSO-d₆) 3.35-3.70 (bm, 8H), 3.82 (s, 3H), 7.14 (d,2H), 7.22 (d, 1H), 7.33 (d, 2H), 7.62-7.68 (dd, 1H), 7.74 (d, 1H), 7.86(d, 1H), 8.10 (bs, 1H), 8.30 (s, 1H), 10.56 (s, 1H); MS base peak at488.2; HPLC purity 92.55%.

N-(4-(4-(pyrazin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(49)

Compound 49 was prepared from quinoline-8-sulfonyl chloride as describedin Scheme 8 using the general procedure provided in Scheme 4.

¹H NMR (500 MHz, DMSO-d₆) 3.35-3.70 (bm, 8H), 7.12 (d, 2H), 7.22 (d,2H), 7.68-7.78 (m, 2H), 7.84 (s, 1H), 8.08 (s, 1H), 8.24 (d, 2H), 8.42(d, 1H), 8.52 (d, 1H), 9.19 (s, 1H), 10.50 (s, 1H); MS base peak at475.2; HPLC purity 98.10%.

Synthesis of Pyridine Analogues

Preparation of Compound 50: To a suspension of NaH (94 mg, 3.94 mmole, 2eq) in DMF (20 mL) was added methyl-2-amino-pyridine-5-carboxylate (300mg, 1.97 mmole, 1 eq) and stirred at room temperature for 30 minutes. Asolution of 5-chloro-2-methoxybenzenesulfonyl chloride (570 mg, 2.36mmole, 1.2 eq) was added slowly at room temperature and stirred for anadditional 2 hrs. The reaction was monitored by TLC which showed 50% ofthe starting material remaining and continuation of the reaction failedto show improvement. The reaction mixture was quenched with water andextracted with ethyl acetate. The organic layer was separated, driedover sodium sulfate and concentrated under reduced pressure. The crudeproduct 50 containing 50% of the starting ester was used without furtherpurificationsd for the next step.

Preparation of Compound 51: To a solution of compound 50 (270 mg) inTHF/H₂O was added lithium hydroxide (0.160 g, 5 eq, 3.786 mmole). Theresulting reaction mixture was heated to reflux and stirred for 4 hrs.Upon completion, the reaction mixture was diluted with water andextracted with ethyl. The aqueous layer was acidified with citric acidand extracted with ethyl acetate. The organic layer was separated anddried over sodium sulfate and concentrated under reduced pressure. Thecrude acid 51 (90 mg, 36% yield) used without further purification.

Preparation of Compound 52: To a solution of compound 51 (90 mg, 0.263mmole, 1 eq) in DMF (15 mL) was added PyBOP (205 mg, 0.395 mmole, 1.5eq) at 0° C. and stirred for 5 minutes. To this, a solution of compound6 (60.2 mg, 0.2635 mmole, 1 eq) in 5 ml of DMF and 3 eq of DIPEA wasadded at 0° C. and stirred at room temperature overnight. Uponcompletion, the excess solvent was removed in vacuo and the residue wasdiluted with water and extracted with ethyl acetate. The organic layerwas separated, washed with water and dried over sodium sulfate andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (60-120 mesh) using 1-2% MeOH/DCM toyield compound 52 in 33% yield (45 mg).

5-Chloro-2-methoxy-N-(5-(4-(2-methoxyphenyl)piperazine-1-carbonyl)pyridin-2-yl)benzenesulfonamide(52)

¹H NMR (500 MHz, DMSO-d₆) 3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.9 (s,6H), 6.90 (s, 2H), 6.92-7.00 (m, 2H), 7.20 (d, 1H), 7.60-7.62 (m, 1H),7.80-7.82 (m, 2H), 8.18 (s, 1H), 11.4 (bs, 1H); MS base peak at 517.2;HPLC purity 97.65%.

N-(5-(4-(2-methoxyphenyl)piperazine-1-carbonyl)pyridin-2-yl)quinoline-8-sulfonamide(53)

¹H NMR (500 MHz, DMSO-d₆) 2.90 (bs, 4H), 3.40-3.70 (b, 4H), 3.80 (s,3H), 6.80-7.20 (m, 5H), 7.60-7.80 (m, 3H), 8.10 (s, 1H), 8.30 (d, 1H),8.50 (d, 2H), 9.0 (s, 1H); MS base peak at 504.2; HPLC purity 98.92%.

Synthesis of Benzyl Analogs

TABLE 2 S. No. R R’ n 60

H 1 61

H 1 62

H 1 63

H 1 64

H 1 65

H 1 66

H 1 67

H 1 68

H 1 69

H 1 70

H 1 71

H 1 72

H 1 73

H 1 74

H 1 75

H 1 76

Na⁺ 1 77

CH₃SO₃— 1 78

H 1 79

H 2 80

H 1 81

H 1 82

H 1 83

H 1

Preparation of Compound 55:

To a solution of ethyl 4-aminobenzoate 6 g, 96.85 mmol in a mixture(1:1) of DCM and pyridine, sulfonyl chloride 54 (27.56 g, 121.07 mmol)was added at room temperature under an N₂ atmosphere. The resultingmixture was allowed to stir for 16 hrs. Upon completion of the reaction,the crude mixture was diluted with DCM, washed with water followed by 1NHCl. The resulting organic layer was then dried over Na₂SO₄ andconcentrated under reduced pressure to afford product 55 in 98% yield(34 g).

Preparation of Compound 56:

To a solution of sulfonamide 55 (34 g, 95.5 mmol) in THF and water (1:1)was added LiOH (20 g, 47.66 mmol). The resulting mixture was allowed tostir at 80° C. overnight. After completion of the reaction, the crudemixture was washed with EtOAc. The aqueous layer was acidified withcitric acid and filtered. The obtained solid was then washed with Et₂Oand azeotroped with toluene under reduced pressure to afford acidproduct 56 (30 g, 95.8% yield).

General procedure for compound 57b-57f (Scheme 11): To a solution ofN-Boc piperazine in DMF, corresponding bromide, R—Br (R=20-23, seeTable 1) was added followed by addition of K₂CO₃. The resulting mixturewas allowed to stir at 80° C. for 3 days. After completion of thereaction, DMF was removed under reduced pressure, the resulting residuewas diluted with water and extracted with EtOAc. The organic layer waswashed with water, dried over Na₂SO₄ and concentrated. The residue waspurified by column chromatography to afford products 57b-57f in goodyields.

Preparation of Compound 57g (Scheme 2): The synthesis of compound 57gwas done from 2-picolinic acid (1.0 g, 8.12 mmol) by following a similarprocedure as described for the preparation of compound 58 in scheme 10by using amine N-Boc piperazine to afford product 57 g in 76.10% yield(1.80 g).

Preparation of Compound 58:

To a solution of acid 56 (2.0 g, 6.09 mmol) in DMF, PyBoP(Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate) (4.75 g, 9.14 mmol) was added at 0° C. and allowedto stir for 5 minutes. This was followed by addition of amine 57a (1.13g, 6.09 mmol) at 0° C. under N2 atmosphere and stirred overnight at roomtemperature. After completion of reaction, the resulting mixture wasdiluted with water and extracted with EtOAc. The organic layer waswashed with water, dried over Na₂SO₄, and evaporated under reducedpressure. The residue was purified by column chromatography (silica gel,60-120 mesh; MeOH-DCM, 2:8) to afford product 58 in 66% yield (2.0 g).

Preparation of Compound 6:

To a solution of MeOH—HCl, Boc protected amine 5 (2 gm, 4.03 mmol) wasadded and the resulting mixture was stirred for 1 hr. After completionof reaction, solvent was removed under reduced pressure, washed withwater followed by addition of NaHCO₃ and extracted with DCM. The organiclayer was dried over Na₂SO₄ and evaporated under reduced pressure toafford product 6 (1.5 gm, 94.30% yield).

Preparation of Compound 60:

To a solution of amine 59 (0.1 g, 0.25 mmoles) and aldehyde 60a (0.04 g,0.27 mmol) in DCM, acetic acid (0.2 mL) was added at room temperatureand the resulting mixture was allowed to stir for 30 min. Then STAB(0.26 g, 1.26 mmol) was added and the resulting mixture was allowed tostir at 50° C. for 1 hr. After completion of reaction, the crude mixturewas diluted with DCM, washed with water, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography (silica gel, 60-120 mesh; MeOH-DCM, 2:8) to affordproduct 60 (0.05 g, 38.40% yield). ¹H NMR (400 MHz, CDCl₃) δ 2.40 (br d,4H), 3.38 (br s, 2H), 3.48 (s, 2H), 3.68 (br s, 2H), 3.80 (s, 3H), 6.79(d, 1H), 6.84 (s, 2H), 7.04 (d, 2H), 7.18 (d, 2H), 7.20-7.28 (m, 2H),7.59-7.64 (m, 2H), 8.03 (d, 1H), 8.28 (d, 1H), 8.36 (d, 1H), 8.58 (s,1H), 9.18 (s, 1H); MS: 517 (M+1 peak).

Preparation of Compound 61:

The synthesis of compound 61 was carried out using compound 59 (0.10 g,0.25 mmol) and following a similar procedure as described for compound60 by using aldehyde 61a to afford product 61 in 30.40% yield (0.040 g).¹H NMR (400 MHz, CDCl₃) δ 2.40 (br d, 4H), 3.38 (br s, 2H), 3.56 (s,2H), 3.68 (br s, 2H), 7.06 (d, 2H), 7.18 (d, 3H), 7.25 (d, 4H), 7.42 (d,2H), 7.59-7.66 (m, 2H), 8.03 (d, 1H), 8.27 (d, 1H), 8.35 (d, 1H), 8.58(s, 1H), 9.18 (s, 1H); MS: 521 (M+1 peak).

Preparation of Compound 62:

The synthesis of compound 62 was carried out utilizing compound 59 (0.08g, 0.20 mmol) by following a similar procedure as described for compound60 by using aldehyde 62a to afford product 62 in 35.00% yield (0.040 g).¹H NMR (400 MHz, CDCl₃) δ 2.40 (br d, 4H), 3.39 (br s, 2H), 3.43 (s,2H), 3.67 (br s, 2H), 7.02 (d, 2H), 7.15-7.21 (m, 2H), 7.48-7.63 (m,2H), 8.03 (d, 1H), 8.31 (d, 2H), 8.39 (d, 1H), 8.58 (s, 1H), 9.18 (s,1H); MS: 567 (M+2 peak).

Preparation of Compound 63:

The synthesis of compound 63 was carried by following a similarprocedure as described for compound 60 using aldehyde 63a to affordproduct 63 in 59.00% yield (0.06 g) from compound 59 (0.08 g, 0.20mmol). ¹H NMR (400 MHz, CDCl₃) δ 2.40 (br d, 4H), 3.39 (br s, 2H), 3.43(s, 2H), 3.67 (br s, 2H), 7.02 (t, 2H), 7.05 (d, 2H), 7.19 (d, 2H), 7.21(s, 2H), 7.49-7.63 (m, 2H), 7.51-7.66 (m, 5H), 8.03 (d, 1H), 8.31 (d,2H), 8.39 (d, 1H), 8.58 (s, 1H), 9.18 (s, 1H); MS: 505 (M+1 peak).

Preparation of Compound 64:

The synthesis of compound 64 was carried out following a similarprocedure as described for compound 60 using aldehyde 64a to affordproduct 64 in 48.54% yield (0.05 g) from compound 59 (0.08 g, 0.20mmol). ¹H NMR (400 MHz, CDCl₃) δ 2.40 (br s, 4H), 3.39 (br s, 2H), 3.58(s, 2H), 3.71 (br s, 2H), 7.08 (d, 2H), 7.16 (d, 2H), 7.43 (d, 1H), 7.51(d, 1H), 7.59-7.68 (m, 4H), 8.04 (d, 1H), 8.31 (d, 2H), 8.39 (d, 1H),8.58 (s, 1H), 9.18 (s, 1H); MS: 512 (M+1 peak).

Preparation of Compound 65:

The synthesis of compound 65 was carried out following a similarprocedure as described for compound 60 using aldehyde 65a to affordproduct 65 in 28.00% yield (0.03 g) from compound 59 (0.08 g, 0.20mmol). ¹H NMR (400 MHz, CDCl₃) δ 2.39 (br d, 4H), 2.58 (s, 3H), 3.29 (brs, 2H), 3.59 (s, 2H), 3.76 (br s, 2H), 7.06 (d, 2H), 7.21 (d, 2H),7.51-7.68 (m, 2H), 7.80 (d, 2H), 8.03 (d, 1H), 8.31 (d, 2H), 8.39 (d,1H), 8.58 (s, 1H), 9.18 (s, 1H); MS: 529 (M+1 peak).

Preparation of Compound 66:

The synthesis of compound 66 was done by following the similar procedureas mentioned for compound 60 by using aldehyde 66a to afford product in38.80% yield (0.04 g) from compound 59 (0.08 g, 0.20 mmol). ¹H NMR (400MHz, CDCl₃) δ 2.40 (br s, 4H), 3.39 (br s, 2H), 3.53 (s, 2H), 3.71 (brs, 2H), 7.06 (d, 2H), 7.15 (d, 2H), 7.43 (t, 1H), 7.51-7.66 (m, 5H),8.03 (d, 1H), 8.31 (d, 2H), 8.39 (d, 1H), 8.58 (s, 1H), 9.18 (s, 1H);MS: 512 (M+1 peak).

Preparation of Compound 67:

The synthesis of compound 67 was carried out following a similarprocedure as described for compound 60 by using aldehyde 67a to affordproduct 38% yield (0.04 g) from compound 59 (0.08 g, 0.20 mmol). ¹H NMR(400 MHz, CDCl₃) δ 2.42 (br d, 4H), 3.38 (br s, 2H), 3.56 (s, 2H), 3.68(br s, 2H), 7.06 (d, 2H), 7.18 (D, 2H), 7.42 (d, 2H), 7.49 (d, 1H),7.59-7.68 (m, 4H), 8.03 (d, 1H), 8.27 (d, 1H), 8.35 (d, 1H), 8.58 (s,1H), 9.18 (s, 1H); MS: 521 (M+1 peak).

Preparation of Compound 68:

The synthesis of compound 68 was carried out by following a similarprocedure described for compound 60 by using aldehyde 68a to afford therequired product in 38% yield (0.04 g) from compound 59 (0.08 g, 0.20mmol). ¹H NMR (400 MHz, CDCl₃) δ 2.43 (br d, 4H), 3.41 (br s, 2H), 3.68(br s, 4H), 7.06 (d, 2H), 7.15 (d, 2H), 7.35-7.42 (m, 1H), 7.50-7.69 (m,5H), 8.03 (d, 1H), 8.31 (d, 2H), 8.39 (d, 1H), 8.58 (s, 1H), 9.18 (s,1H); MS: 512 (M+1 peak).

Preparation of Compound 69:

The synthesis of compound 69 was done by following the similar procedureas mentioned for compound 60 by using aldehyde 69a to afford therequired product in 37.70% yield (0.04 g) from compound 59 (0.08 g, 0.20mmol). ¹H NMR (400 MHz, CDCl₃) δ 2.39 (br s, 4H), 2.52 (s, 3H), 3.26 (brs, 2H), 3.61 (br s, 2H), 3.65 (s, 2H), 7.06 (d, 2H), 7.15 (d, 2H),7.29-7.39 (m, 3H), 7.58-7.63 (m, 2H), 7.80 (d, 1H), 8.03 (d, 1H), 8.31(d, 2H), 8.39 (d, 1H), 8.58 (s, 1H), 9.18 (s, 1H); MS: 529 (M+1 peak).

Preparation of Compound 70

The synthesis of compound 70 was carried out following a similarprocedure as described for compound 60 by using aldehyde 70a to affordthe product in 28.50% yield (0.03 gm) from compound 6 (0.08 gm, 0.20mmol). ¹H NMR (400 MHz, CDCl₃) δ 2.42 (br d, 4H), 3.35 (br s, 2H), 3.60(s, 2H), 3.68 (br s, 2H), 7.03 (d, 2H), 7.08-7.26 (m, 4H), 7.32 (d, 1H),7.39 (d, 1H), 7.54-7.60 (m, 2H), 8.03 (d, 1H), 8.28 (d, 1H), 8.37 (d,1H), 8.58 (s, 1H), 9.18 (s, 1H); MS: 521 (M+1 peak).

Preparation of Compound 71:

The synthesis of compound 71 was carried out following a similarprocedure as described for compound 60 by using aldehyde 71a to affordthe required product in 57.00% yield (0.06 g) from compound 59 (0.08 g,0.20 mmol). ¹H NMR (400 MHz, CDCl₃) δ 2.39 (br d, 4H), 3.38 (br s, 2H),3.43 (s, 2H), 3.63 (br s, 2H), 7.06 (d, 2H), 7.17 (d, 2H), 7.21-7.29 (m,2H), 7.58-7.63 (m, 3H), 8.03 (d, 1H), 8.31 (d, 2H), 8.39 (d, 1H), 8.58(s, 1H), 9.18 (s, 1H); MS: 522 (M+ peak).

Synthesis of Compound 72:

The synthesis of compound 72 was carried out following a similarprocedure as described for compound 7a by using aldehyde 72a to affordthe product in 38.80% yield (0.04 g) from compound 59 (0.08 g, 0.20mmol). ¹H NMR (400 MHz, CDCl₃): δ 2.45 (br s, 4H), 3.41 (br s, 2H), 3.60(s, 2H), 3.68 (br s, 2H), 7.06 (d, 2H), 7.15 (d, 2H), 7.21-7.29 (m, 1H),7.58-7.63 (m, 2H), 7.80 (d, 1H), 8.03 (d, 1H), 8.31 (d, 2H), 8.39 (d,1H), 8.58 (s, 1H), 9.18 (s, 1H); MS: 522 (M+ peak).

Preparation of Compound 73:

The synthesis of compound 73 was carried out following a similarprocedure as described for compound 58 in scheme 10 by using amine 57bto afford product 73 in 73.27% yield (0.08 g) from compound 56 (0.08 g,0.24 mmoles). ¹H NMR (400 MHz, CDCl₃): δ 3.44 (br s, 4H), 3.62 (s, 2H),3.76 (br s, 4H), 6.84 (d, 1H), 7.12 (d, 2H), 7.21 (d, 2H), 7.37 (d, 1H),7.60-7.66 (m, 2H), 8.04 (d, 1H), 8.32 (d, 1H), 8.39 (d, 1H), 9.18 (d,1H); MS: 480 (M+1 peak).

Preparation of Compound 74:

The synthesis of compound 74 was carried out following a similarprocedure as described for compound 58 in scheme 10 by using amine 57cto afford product 74 in 33.45% yield (0.09 g) from compound 56 (0.18 g,0.54 mmol). ¹H NMR (400 MHz, DMSO-d₆): δ 2.45 (s, 3H), 2.99 (br s, 4H),3.55 (br s, 4H), 6.78 (s, 1H), 7.14 (dd, 4H), 7.66-7.75 (m, 2H), 8.26(d, 1H), 8.41 (d, 1H), 8.50 (d, 1H), 9.16 (d, 1H); MS: 480 (M+1 peak).

Preparation of Compound 75:

The synthesis of compound 75 was done by following the similar procedureas mentioned for compound 58 in scheme 10 by using amine 57d to affordproduct 75 in 43.85% yield (0.10 g) from compound 56 (0.15 g, 0.47mmol). ¹H NMR (400 MHz, CDl₃): δ 2.40 (br d, 4H), 3.38 (br s, 2H), 3.52(s, 2H), 3.73 (br s, 2H), 7.07 (d, 2H), 7.18 (d, 2H), 7.22-7.38 (m, 8H),7.59-7.63 (m, 2H), 8.02 (d, 1H), 8.32 (d, 1H), 8.39 (d, 1H), 9.18 (d,1H), 8.58 (s, 1H), 9.18 (s, 1H); MS: 487 (M+1 peak).

Preparation of Compound 76:

The synthesis of compound 76 was carried out following a similarprocedure as described for compound 58 in scheme 10 by using amine 57eto afford product 76 in 26.31% yield (0.06 g) from compound 56 (0.23 g,0.70 mmol). ¹H NMR (400 MHz, CDCl₃): δ 3.15 (br s, 4H), 3.82 (br s, 4H),4.21 (s, 2H), 7.12 (dd, 4H), 7.41 (t, 1H), 7.52-7.67 (m, 3H), 7.82 (t,1H), 8.04 (d, 1H), 8.31 (d, 1H), 8.39 (d, 1H), 8.63 (d, 2H), 9.16 (d,1H); MS: 480 (M+1 peak); MS: 488 (M+1 peak).

Preparation of Compound 77:

The synthesis of compound 7 was carried out following a similarprocedure as described for compound 58 in scheme 10 by using amine 57fto afford product 77 in 21.14% yield (0.07 g) from compound 56 (0.17 g,0.51 mmol). ¹H NMR (400 MHz, CDCl₃): δ 1.71 (br s, 1H), 1.80 (br s, 1H),2.53 (br d, 2H), 2.71 (br d, 2H), 3.38 (br s, 2H), 3.57-3.69 (m, 4H),7.02 (t, 2H), 7.16 (t, 2H), 7.59-7.63 (m, 2H), 8.01 (d, 1H), 8.31 (d,1H), 8.39 (d, 1H), 8.48 (s, 1H), 9.16 (d, 1H); MS: 480 (M+1 peak); MS:501 (M+1 peak).

Preparation of Compound 78:

The synthesis of compound 78 was carried out following a similarprocedure as described for compound 60 in scheme 10 by using aldehyde 24to afford the required product in 48.61% yield (0.035 g) from compound59 (0.07 g, 0.16 mmol). ¹H NMR (400 MHz, CDCl₃): δ 0.04 (d, 2H), 0.54(d, 2H), 0.80-0.90 (m 1H), 2.24 (d, 2H), 2.48 (br d, 4H), 3.39 (br s,2H), 3.78 (br s, 2H), 7.12 (dd, 4H), 7.49-7.64 (m, 2H), 8.04 (d, 1H),8.31 (d, 1H), 8.39 (d, 1H), 8.58 (s, 1H), 9.16 (d, 1H); MS: 480 (M+1peak); MS: 451 (M+1 peak).

Preparation of Compound 81

The synthesis of compound 81 was carried out following a similarprocedure as described for compound 60 in scheme 10 by using aldehyde81a to afford product 81 in 43.26% yield (0.045 g) from compound 6 (0.1g, 0.23 mmol). ¹H NMR (400 MHz, CDCl₃): δ 0.91 (t, 3H), 1.25-1.39 (m,2H), 1.40-1.49 (m, 2H), 2.30 (t, 2H), 2.42 (br s, 4H), 3.39 (br s, 2H),3.70 (br s, 2H), 7.05 (d, 2H), 7.16 (d, 2H), 7.59-7.64 (m, 2H), 8.02 (d,1H), 8.32 (d, 1H), 8.38 (d, 1H), 8.58 (br s, 1H), 9.16 (d, 1H); MS: 480(M+1 peak); MS: 453 (M+1 peak).

Preparation of Compound 82:

The synthesis of compound 82 was carried out following a similarprocedure as described for compound 60 in scheme 10 by using aldehyde82a to afford product in 48.73% yield (0.06 g) from compound 59 (0.08 g,0.20 mmol). ¹H NMR (400 MHz, CDCl₃): δ 2.39 (br s, 2H), 2.56 (br s, 2H),3.39 (br s, 2H), 3.59 (s, 2H), 3.75 (br s, 2H), 3.81 (s, 3H), 6.85 (d,1H), 6.92 (t, 1H), 7.08 (d, 2H), 7.17 (d, 2H), 7.24-7.31 (m, 2H), 8.02(d, 1H), 8.32 (d, 1H), 8.38 (d, 1H), 8.58 (br s, 1H), 9.17 (d, 1H); MS:480 (M+1 peak); MS: 517 (M+1 peak).

Preparation of Compound 83:

The synthesis of compound 83 was carried out following a similarprocedure as described for compound 58 in scheme 10 by using amine 57gto afford product in 22.72% yield (0.05 gm) from compound 56 (0.14 gm,0.43 mmol). ¹H NMR (400 MHz, CDCl₃): δ 3.62 (br s, 8H), 7.05 (d, 2H),7.19 (d, 2H), 7.38 (t, 1H), 7.59-7.64 (m, 2H), 7.69 (d, 1H), 7.80 (t,1H), 8.02 (d, 1H), 8.32 (d, 1H), 8.38 (d, 1H), 8.58 (br s, 1H), 9.17 (d,1H); MS: 480 (M+1 peak); MS: 502 (M+1 peak).

Preparation of Sodium Salt 76:

To a solution of sulfonamide 75 (0.05 g, 0.10 mmol) in Methanol, NaOH(0.04 g, 0.10 mmol) was added at room temperature and the resultingmixture was allowed to stir for 2 hrs. After completion of the reaction,the corresponding solvent was removed under reduced pressure. This wasfollowed by the addition of Et₂O (5 mL) and its subsequent removal. Theaddition and removal of Et₂O was carried out several times to afford thedesired product as a solid in 84.61% yield (0.04 g). ¹H NMR (400 MHz,DMSO-d₆): δ 3.40 (br s, 2H), 3.59 (br s, 8H), 6.77 (d, 1H), 6.89 (d,1H), 7.18-7.29 (m, 2H), 7.50-7.60 (m, 2H), 7.99 (d, 1H), 8.25-8.32 (m,2H), 8.98 (d, 1H); MS: 509 (M+1 peak).

Preparation of Mesylate Salt 77:

To a solution of sulfonamide 75 (0.05 g, 0.10 mmol) in DCM, CH₃SO₃H(0.10 g, 0.10 mmol) was added at room temperature and the resultingmixture was allowed to stir for 2 hrs. After completion of the reaction,the corresponding solvent was removed under reduced pressure followed bythe addition of Et₂O was added (5 mL) and it subsequent removal. Theaddition and removal of Et₂O was carried out several times (3×5 mL) toafford the desired product in 59.32% yield (0.035 gm). ¹H NMR (400 MHz,CDCl₃): δ 3.02 (br s, 3H), 3.25 (br s, 3H), 4.23 (s, 2H), 7.17 (dd, 4H),7.62-7.69 (m, 2H), 8.22 (d, 1H), 8.32 (d, 1H), 8.38 (d, 1H), 9.10 (d,1H); MS: 487 (M+ peak).

Synthesis of N⁴-Aryl/Heteroaryl Piperazine Analogues

General Procedure for Compound 86: Nitrogen was purged through a stirredsolution of arylbromide (84, 2.15 mmol) in 1,4-dioxane (20 ml) at roomtemperature for 30 min. BINAP (0.134 g, 0.215 mmol), palladium acetate(0.0096 g, 0.043 mmol) and cesium carbonate (1.40 g, 4.3 mmol) wereadded to the reaction mixture and the nitrogen purging was continued foranother 20 min. and finally N-Boc piperazine (85, 0.4 g, 2.15 mmol) wasadded and stirred at 100° C. overnight under nitrogen atmosphere. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasconcentrated under vacuum. The residue was dissolved in water, extractedwith ethyl acetate (3×50 ml). Combined organic extracts were washed withbrine (20 ml), dried over anhydrous Sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was then purifiedby column chromatography (60-120 silica gel) using 10% ethylacetate-hexane to yield compound 86 (40-60%).

General Procedure for Compound 87: N¹-Boc-N⁴-arylpiperazine (86, 1.075mmol) was taken into a round bottomed flask and was added methanolic-HCl(20 ml, 20%) which resulted in formation of a homogeneous solution andwas stirred for 1 h at room temperature. After completion of thereaction (monitored by TLC), the solvent was removed under vacuum. Thecrude product was washed with ethyl acetate repeatedly and then driedwell to obtain compound 87 (90%) as a white solid.

Procedure for preparation of ethyl 4-(quinoline-8-sulfonamido)benzoate90: To a solution of ethyl-4-amino benzoate (88, 5.0 g, 30.16 mmol) in a1:1 mixture of DCM-pyridine (50:50 ml) was added quinoline-8-sulfonylchloride (89, 8.24 g, 36.19 mmol) under nitrogen atmosphere. Theresultant solution was stirred overnight at room temperature. Oncompletion of the reaction (monitored by TLC), the reaction mixture wasdiluted with dichloromethane (150 ml), washed with water (3×50 ml), 1NHCl solution (3×50 ml) and brine (50 ml. The combined organic extractswere dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. Crude product was co-distilled with toluene to remove theremnants of pyridine and dried to yield sulfonamide 90 (11.58 g, 90%) asan off-white solid and was used as such for the next step withoutfurther purification.

Analytical data for compound 90: ¹H NMR (500 MHz, CDCl₃) δ:1.20 (3H, t),4.19 (2H, q), 7.20 (2H, m), 7.60-7.80 (4H, m), 8.30 (1H, m), 8.40-8.50(2H, m), 9.10 (1H, m), 10.8 (1H, s); MS: m/z 357.4 (M+1)⁺.

Procedure for preparation of 4-(quinoline-8-sulfonamido)benzoic acid 91:Ethyl 4-(quinoline-8-sulfonamido)benzoate (90, 10 g, 28.08 mmol) wasdissolved in a mixture of THF-water (100:100 ml) and maintained at roomtemperature. To this solution was added LiOH (5.89 g, 14.0 mmol) and theresultant solution was refluxed overnight. The reaction mixture was thenwashed with ethyl acetate (3×50 ml) and then acidified with dilute HCl.The resultant suspension was filtered and residue was co-distilled withtoluene. This product was then dried under vacuum to yield carboxylicacid 91 (8.28 g, 90%) as an off-white solid.

Analytical data for compound 91: ¹H NMR (500 MHz, CDCl₃) δ: 7.10 (2H,m), 7.60-7.80 (4H, m), 8.25 (1H, m), 8.40-8.60 (2H, m), 9.10 (1H, m),10.7 (1H, bs), 12.6 (1H, bs); MS: m/z 329.3 (M+1)⁺.

General Procedure for Compound 92: To a stirred solution of thecarboxylic acid (91, 0.61 mmol) in DMF at 0° C. under nitrogenatmosphere, EDCI (0.129 gm, 0.671 mmol), HOBt (0.91 gm, 0.671 mmol) andDIPEA (0.31 ml, 1.83 mmol) were added and the resultant solution wasstirred at room temperature for 30 min. Amine hydrochloride (87, 0.61mmol) was then added at 0° C. and stirred overnight at room temperature.After completion of the reaction (monitored by TLC), the reactionmixture was poured into 1.0 M HCl and extracted with EtOAc. The organiclayer was washed with saturated NaHCO₃ solution, dried over NaSO4 andfiltered. The solvent was removed by rotary evaporation and the productwas isolated by chromatography on silica gel (60-120 silica gel, 2%MeOH-DCM) or preparative HPLC to yield amide (92a-as) (40-60%) as anoff-white solid.

General Procedure for Compound (92at, 92au & 92av): To a solution ofN⁴-aryl piperazine analogue (0.39 mmol) in methanol-DCM mixture (forSodium salt) or DCM (for mesylate salt) was added sodium hydroxide inmethanol (0.39 mmol) or methanesulfonylchloride (0.39 mmol). Thereaction mixture was stirred over night and evaporated the solvent underreduced pressure. The crude residue was then washed sequentially withether and n-pentane to yield desired salt as white solid.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92a)

¹H NMR (500 MHz, DMSO-d₆) δ:10.42 (s, 1H), 9.15 (bs, 1H), 8.50 (d, 1H),8.40 (d, 1H), 8.24 (d, 1H), 7.70-7.80 (m, 2H), 7.15-7.20 (dd, 4H),6.90-7.00 (m, 2H), 6.82 (d, 2H), 3.80 (s, 3H), 3.40-3.78 (bm, 4H),2.80-3.00 (bs, 4H); HPLC purity: 97.11%; MS, m/z found 503.2 (M+1)⁺.

N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide (92b)

¹H NMR (500 MHz, DMSO-d₆) δ:10.42 (s, 1H), 9.18 (d, 1H), 8.56 (d, 1H),8.44 (d, 1H), 8.30 (d, 1H), 7.70-7.80 (m, 2H), 7.10-7.22 (m, 6H), 6.90(d, 2H), 6.80 (t, 1H), 3.30-3.70 (bs, 4H), 3.00-3.20 (bm, 4H); HPLCpurity 98.50%: MS, m/z found 473.2 (M+1)⁺.

N-(4-(4-(3-ethoxyphenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92c)

¹H NMR (400 MHz, CDCl₃) δ: 9.18 (d, 1H), 8.60 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.10 (d, 1H), 7.65 (m, 2H), 7.05-7.20 (m, 5H), 6.50 (m,3H), 4.00 (q, 2H), 3.40-3.90 (bs, 4H), 3.00-3.20 (bm, 4H), 1.40 (t, 3H);HPLC purity 99.74%: MS, m/z found 517.40 (M+1)⁺.

N-(4-(4-(4-ethoxyphenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92d)

¹H NMR (400 MHz, CDCl₃) δ: 9.18 (d, 1H), 8.60 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (d, 2H), 7.10 (d, 2H),6.85 (m, 4H), 4.00 (q, 2H), 3.40-3.90 (bm, 4H), 3.00 (bm, 4H), 1.4 (t,3H); HPLC purity 99.36%: MS, m/z found 517.40 (M+1)⁺.

Ethyl 3-(4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)benzoate(92e)

¹H NMR (400 MHz, CDCl₃) δ: 9.20 (d, 1H), 8.60 (s, 1H), 8.40 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 4H), 7.30 (m, 1H), 7.20 (d, 2H),7.10 (m, 3H), 4.40 (q, 2H), 3.40-3.90 (bm, 4H), 3.20 (bm, 4H), 1.4 (t,3H); HPLC purity 99.65%: MS, m/z found 545.35 (M+1)⁺.

N-(4-(4-(2-fluorophenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92f)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.60 (s, 1H), 8.40 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (m, 3H), 7.10 (d, 2H),6.65 (d, 1H), 6.55 (m, 2H), 3.40-3.80 (bm, 4H), 3.15 (bm, 4H); HPLCpurity 99.16%: MS, m/z found 491.35 (M+1)⁺.

N-(4-(4-(3-isopropoxyphenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92g)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.60 (s, 1H), 8.40 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (m, 2H), 7.15 (m, 1H),7.10 (d, 2H), 6.45 (m, 3H), 3.40-3.80 (bm, 4H), 3.15 (bm, 4H); HPLCpurity 99.45%: MS, m/z found 531.40 (M+1)⁺.

N-(4-(4-(2,5-difluorophenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92h)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.60 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (m, 2H), 7.10 (d, 2H),6.95 (m, 1H), 6.60 (m, 2H), 3.45-3.90 (bm, 4H), 3.00 (bm, 4H); HPLCpurity 99.94%: MS, m/z found 509.30 (M+1)⁺.

N-(4-(4-(3-(methylthio)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92i)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.60 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (m, 3H), 7.10 (d, 2H),6.80 (m, 2H), 6.65 (d, 1H), 3.45-3.90 (bm, 4H), 3.10 (bm, 4H), 2.45 (s,3H); HPLC purity 99.98%: MS, m/z found 519.30 (M+1)⁺.

N-(4-(4-(3-(trifluoromethyl)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92j)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.60 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.50 (d, 2H), 7.20 (m, 2H),7.10 (d, 2H), 6.90 (d, 2H), 3.45-3.90 (bm, 4H), 3.10 (bm, 4H); HPLCpurity 99.63%: MS, m/z found 541.25 (M+1)⁺.

N-(4-(4-(2-(trifluoromethoxy)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92k)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (m, 4H), 6.95-7.15 (m,4H), 3.45-3.90 (bm, 4H), 3.10 (bm, 4H); HPLC purity 99.89%: MS, m/zfound 557.35 (M+1)⁺.

N-(4-(4-(4-(ethylthio)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92l)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.3 (d, 2H), 7.20 (d, 2H),7.10 (d, 2H), 6.80 (d, 2H), 3.45-3.90 (bm, 4H), 3.10 (bm, 4H), 2.90 (q,2H), 1.15 (t, 3H); HPLC purity 98.53%: MS, m/z found 533.35 (M+1)⁺.

N-(4-(4-(4-(methylthio)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92m)

¹H NMR (400 MHz, DMSO-d₆) δ: 10.40 (s, 1H), 9.15 (s, 1H), 8.50 (d, 1H),8.40 (d, 1H), 8.30 (d, 1H), 7.70 (m, 2H), 7.20 (m, 6H), 6.85 (d, 2H),3.20-3.70 (bm, 4H), 3.05 (bm, 4H), 2.35 (s, 3H); HPLC purity 91.00%: MS,m/z found 518.50 (M+1)⁺.

N-(4-(4-(3-(methoxy)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92n)

¹H NMR (400 MHz, DMSO-d₆) δ:10.45 (s, 1H), 9.05 (d, 1H), 8.50 (d, 1H),8.45 (d, 1H), 8.30 (d, 1H), 7.70 (m, 2H), 70.20 (m, 5H), 6.50 (d, 1H),6.40 (s, 1H), 6.35 (d, 1H), 3.65 (s, 3H), 3.20-3.70 (bm, 4H), 3.05 (bm,4H); LCMS purity 100.00%: MS, m/z found 503.35 (M+1)⁺.

N-(4-(4-(3-(chloro)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92o)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (s, 1H), 8.60 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.10-7.20 (m, 5H), 6.85 (m,2H), 6.75 (d, 1H), 3.40-3.85 (bm, 4H), 3.10 (bm, 4H); LCMS purity97.15%: MS, m/z found 507.30 (M+1)⁺.

N-(4-(4-(3-(methyl)-5-(trifluoromethyl)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92p)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20-7.30 (m, 4H), 7.15 (s,1H), 7.10 (d, 2H), 3.40-3.85 (bm, 4H), 2.85 (bm, 4H), 2.35 (s, 3H); LCMSpurity 99.65%: MS, m/z found 555.35 (M+1)⁺.

N-(4-(4-(3,4-(dichloro)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92q)

¹H NMR (400 MHz, DMSO-d₆) δ:10.45 (s, 1H), 9.15 (s, 1H), 8.50 (d, 1H),8.40 (d, 1H), 8.30 (d, 1H), 7.75 (m, 2H), 7.4 (d, 1H), 7.10-7.20 (m,5H), 6.90 (d, 1H), 3.20-3.65 (bm, 4H), 3.10 (bs, 4H); HPLC purity93.48%: MS, m/z found 542.35 (M+1)⁺.

N-(4-(4-(3-(trifluoromethoxy)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92r)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (d, 2H), 7.10 (m, 4H),6.85 (d, 2H), 3.40-3.90 (bm, 4H), 3.10 (bs, 4H); HPLC purity 90.37%: MS,m/z found 557.50 (M+1)⁺.

N-(4-(4-(4-(N,N-diethylamino)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92s)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (d, 2H), 7.10 (d, 2H),6.85 (d, 2H), 6.65 (d, 2H), 3.40-3.90 (bm, 4H), 3.3 (q, 4H), 2.80-3.10(bm, 4H), 1.1 (t, 6H); HPLC purity 97.59%: MS, m/z found 544.50 (M+1)⁺.

N-(4-(4-(3,4-(difluoro)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92t)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (d, 2H), 7.10 (d, 2H),7.05 (m, 1H), 6.65 (m, 1H), 6.55 (d, 1H), 3.40-3.90 (bm, 4H), 3.00 (bs,4H); HPLC purity 99.73%: MS, m/z found 509.55 (M+1)⁺.

N-(4-(4-(4-(fluoro)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92u)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (d, 2H), 7.10 (d, 2H),6.95 (m, 2H), 6.85 (m, 2H), 3.40-3.90 (bm, 4H), 3.00 (bs, 4H); HPLCpurity 97.39%: MS, m/z found 491.25 (M+1)⁺.

N-(4-(4-(2-(ethyl)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92v)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.05-7.30 (m, 7H), 7.00 (d,1H), 3.40-3.90 (bm, 4H), 2.80 (bm, 4H), 2.7 (q, 2H), 1.20 (t, 3H); HPLCpurity 98.85%: MS, m/z found 501.05 (M+1)⁺.

N-(4-(4-(4-(chloro)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92w)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (m, 4H), 7.10 (d, 2H),6.80 (d, 2H), 3.40-3.90 (bm, 4H), 3.10 (bm, 4H); LCMS purity 99.88%: MS,m/z found 507.25 (M+1)⁺.

N-(4-(4-(3-(ethyl)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92x)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.20 (m, 3H), 7.10 (d, 2H),6.75 (m, 3H), 3.40-3.90 (bm, 4H), 3.10 (bm, 4H), 2.6 (q, 2H), 1.2 (t,3H); LCMS purity 96.79%: MS, m/z found 501.30 (M+1)⁺.

N-(4-(4-(3-(trifluoromethyl)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92y)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.55 (s, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.60 (m, 2H), 7.50 (m, 2H), 7.25 (m, 2H),7.20 (m, 2H), 7.10 (d, 2H) 3.40-3.90 (bm, 4H), 2.90 (bm, 4H); HPLCpurity 99.65%: MS, m/z found 541.15 (M+1)⁺.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)-N-methylquinoline-8-sulfonamide(92z)

¹H NMR (500 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 8.55 (m, 1H), 8.3 (m, 2H),7.7 (m, 2H), 7.25 (m, 4H), 6.95 (m, 2H), 6.85 (m, 2H), 3.78 (s, 3H), 3.6(s, 3H), 3.30-3.80 (bm, 4H), 2.80-3.00 (bm, 4H); HPLC purity 97.68%: MS,m/z found 517.3 (M+1)⁺.

Ethyl2-(4-(4-(N-methylquinoline-8-sulfonamido)benzoyl)piperazin-1-yl)benzoate(92aa)

¹H NMR (400 MHz, DMSO-d₆) δ:10.43 (s, 1H), 9.18 (s, 1H), 8.55 (d, 1H),8.41 (d, 1H), 8.23 (d, 1H), 7.7 (m, 2H), 7.55 (m, 1H), 7.41 (m, 1H),7.25 (m, 6H), 4.22 (q, 2H), 3.30-3.80 (bm, 4H), 2.80-3.00 (bm, 4H), 1.25(t, 3H); LCMS purity 97.43%: MS, m/z found 545.1 (M+1)⁺, 567.1 (M+23).

N-(4-(4-(3-(dimethylamino)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92ab)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.11-9.16 (d, 1H), 8.54 (bs, 1H), 8.22-8.55(d, 2H), 8.02-8.06 (d, 1H), 7.55-7.64 (m, 2H), 7.02-7.32 (m, 6H),6.20-6.54 (m, 2H), 3.20-3.94 (m, 4H), 3.00-3.22 (bs, 4H), 2.84-2.94 (s,6H); LCMS purity 98.33%: MS, m/z found 516.3 (M+1)⁺, 538.3 (M+23).

N-(4-(4-(3-fluorophenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92ac)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.10-9.15 (d, 1H), 8.22-8.40 (m, 2H),7.98-8.11 (d, 1H), 7.52-7.66 (m, 2H), 7.02-7.28 (m, 6H), 6.42-6.64 (m,3H), 3.42-3.84 (bd, 4H), 3.00-3.22 (m, 4H); LCMS purity 93.74%: MS, m/zfound 491.3 (M+1)⁺.

N-(4-(4-(5-isopropyl-2-methylphenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide-(92ad)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.18 (d, 1H), 8.54 (bs, 1H), 8.24-8.38 (dd,2H), 8.00-8.15 (d, 1H), 7.54-7.66 (m, 2H), 7.18-7.26 (m, 2H), 7.02-7.14(m, 3H), 6.86-6.94 (m, 2H), 3.42-3.92 (bd, 4H), 2.80-2.98 (m, 2H), 2.22(s, 3H), 1.14-1.24 (d, 6H), 0.80-0.92 (m, 1H); HPLC purity 98.76%:

N-(4-(4-(4-(trifluoromethoxy)phenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide-(92ae)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.18 (d, 1H), 8.58 (bs, 1H), 8.23-8.38 (dd,2H), 8.00-8.15 (d, 1H), 7.52-7.68 (m, 2H), 7.14-7.24 (m, 6H), 6.80-6.89(d, 2H), 3.42-3.92 (bd, 4H), 3.00-3.18 (bs, 4H); HPLC purity 98.77%:

N-(4-(4-(4-methoxyphenyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92af)

¹H NMR (400 MHz, DMSO-d₆) δ:10.41 (s, 1H), 9.17 (s, 1H), 8.21-8.45 (ddd,3H), 7.63-7.78 (m, 2H), 7.12-7.24 (m, 4H), 6.78-6.94 (d, 4H), 3.82 (s,3H), 3.22-3.54 (m, 4H), 2.84-3.08 (m, 4H); LCMS purity=93.70%: MS, m/zfound 503.1 (M+1)⁺.

5-(4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)pyridin-3-ylpropionate(92ag)

¹H NMR (400 MHz, CDCl₃) δ: 10.42 (s, 1H), 9.15 (s, 1H), 8.40-8.54 (dt,2H), 8.24-8.28 (d, 1H), 7.60-7.72 (m, 3H), 7.05-7.22 (m, 4H), 4.21-4.38(q, 2H), 3.3-3.8 (m, 8H), 1.25 (t, 3H); LCMS purity: 98.85%; MS, m/zfound 546.3 (M+1)⁺.

N-(4-(4-(thiazol-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92ah)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.40 (d, 1H), 8.30 (d, 1H),8.05 (d, 1H), 7.60 (m, 2H), 7.35 (d, 1H), 7.20 (d, 2H), 7.10 (d, 2H),6.7 (d, 1H), 3.3-3.8 (m, 8H); HPLC purity: 99.79%; MS, m/z found 480.2(M+1)⁺.

N-(4-(4-(2-methylthiazol-5-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92ai)

¹H NMR (400 MHz, CDCl₃) δ: 10.42 (s, 1H), 9.15 (d, 1H), 8.45 (d, 1H),8.40 (d, 1H), 8.15 (d, 1H), 7.70 (m, 2H), 7.20 (d, 2H), 7.15 (d, 2H),6.8 (s, 1H), 3.5 (bm, 4H), 2.95 (bm, 4H), 2.4 (s, 3H); HPLC purity:95.78%; MS, m/z found 494.3 (M+1)⁺.

N-(4-(4-(pyrazin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92aj)

¹H NMR (500 MHz, DMSO-d₆) δ:10.42 (s, 1H), 9.15 (s, 1H), 8.52 (d, 1H),8.44 (d, 1H), 8.3 (m, 2H), 8.1 (s, 1H), 7.86 (s, 1H), 7.74 (m, 2H), 7.23(d, 2H), 7.14 (d, 2H), 3.3-3.7 (m, 8H); HPLC purity: 98.10%; MS, m/zfound 475.2 (M+1)⁺.

N-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92ak)

¹H NMR (500 MHz, DMSO-d₆) δ:10.42 (s, 1H), 9.15 (s, 1H), 8.52 (d, 1H),8.45 (d, 1H), 8.35 (d, 2H), 8.30 (d, 1H), 7.75 (m, 2H), 7.20 (d, 2H),7.15 (d, 2H), 7.80 (t, 1H), 3.3-3.8 (m, 8H); HPLC purity: 99.52%; MS,m/z found 475.2 (M+1)⁺.

N-(4-(4-(2-methoxypyridin-3-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92al)

¹H NMR (500 MHz, DMSO-d₆) 2.80-3.00 (4H, m), 3.40-3.85 (4H, m), 3.85(3H, s), 6.91 (1H, m), 7.11-7.20 (5H, m), 7.70-7.75 (3H, m), 8.27-8.29(1H, m), 8.41-8.53 (2H, m), 9.12 (1H, m), 10.44 (1H, s). MS 504.1(M+1)⁺.

N-(4-(4-(4-methoxypyridin-3-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92am)

¹H NMR (400 MHz, CDCl₃) δ: 9.18 (d, 1H), 8.60 (bs, 1H), 8.25-8.40 (m,3H), 8.05 (d, 1H), 7.65 (m, 2H), 7.20 (d, 2H), 7.15 (d, 2H), 7.10 (d,1H), 4.10 (s, 3H), 3.40-3.80 (bm, 4H), 3.10 (bm, 4H); HPLC purity:97.14%; LCMS, m/z found 504.35 (M+1)⁺.

N-(4-(4-(5-(ethoxycarbonyl)pyridin-3-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92an)

¹H NMR (400 MHz, DMSO-d₆) δ:10.45 (s, 1H), 9.15 (d, 1H), 8.55 (m, 3H),8.45 (d, 1H), 8.30 (d, 1H), 7.70 (m, 2H), 7.65 (s, 1H), 7.20 (d, 2H),7.10 (d, 2H), 4.30 (q, 2H), 3.4-3.8 (bm, 4H), 3.1 (bm, 4H), 1.3 (t, 3H);LCMS purity: 98.85%; MS, m/z found 546.35 (M+1)⁺.

N-(4-(4-(5-(methoxycarbonyl)-6-methoxy)pyridin-3-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide (92ao)

¹H NMR (400 MHz, CDCl₃) δ: 9.18 (d, 1H), 8.60 (bs, 1H), 8.35 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.95 (d, 1H), 7.80 (d, 1H), 7.60 (m, 2H),7.20 (d, 2H), 7.10 (d, 2H), 4.00 (s, 3H), 3.9 (s, 3H), 3.4-3.8 (bm, 4H),3.1 (bm, 4H); HPLC purity: 94.72%; MS, m/z found 562.18 (M+1)⁺.

N-(4-(4-(pyridin-4-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92ap)

¹H NMR (400 MHz, CDCl₃) δ: 9.2 (s, 1H), 8.22-8.40 (m, 4H), 8.00-8.04 (m,1H), 7.54-7.62 (m, 2H), 7.05-7.22 (dd, 4H), 6.60-6.68 (d, 1H), 3.2-3.8(m, 8H); LCMS purity: 97.37%; LCMS, m/z found 474.05 (M+1)⁺.

N-(4-(4-(3-methoxypyridin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92aq)

¹H NMR (400 MHz, CDCl₃) δ:10.22 (s, 1H), 9.14 (d, 1H), 8.22-8.50 (ddd,3H), 7.62-7.78 (m, 3H), 7.11-7.22 (m, 5H), 6.82-6.86 (d, 1H), 3.7 (s,3H), 3.2-3.8 (m, 8H); LCMS purity: 97.96%; LCMS, m/z found 504.3 (M+1)⁺.

N-(4-(4-(2-methoxypyridin-3-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92ar)

¹H NMR (400 MHz, CDCl₃) δ: 10.21 (s, 1H), 9.12-9.13 (d, 1H), 8.27-8.53(ddd, 3H), 7.70-7.75 (m, 3H), 7.13-7.20 (m, 5H), 6.87-6.90 (dd, 1H),3.85 (s, 3H), 3.29-3.50 (m, 4H), 2.92 (bn, 4H); LCMS purity 97.11%;LCMS, m/z found 504.3 (M+1)⁺.

N-(4-(4-(isoquinolin-4-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(92as)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.18 (d, 1H), 9.01 (s, 1H), 8.52-8.58 (s,1H), 8.25-8.41 (dd, 2H), 7.98-8.18 (m, 4H), 7.54-7.78 (m, 4H), 7.22-7.28(d, 2H), 7.02-7.16 (d, 2H), 3.82-3.98 (m, 4H), 2.94-3.22 (bs, 4H); HPLCpurity 94.23%; MS m/z found 524.25 (M+1)⁺.

Sodium(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)phenyl)(quinolin-8-ylsulfonyl)amide (92at)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.00 (s, 1H), 8.40 (m, 2H), 8.00 (d, 1H),7.60 (m, 2H), 6.90-7.00 (m, 4H), 6.80 (m, 4H), 3.75 (s, 3H), 3.55 (bs,4H), 2.90 (bs, 4H); LCMS purity: 95.17%; MS, m/z found 503.25 (M-Na+1)⁺.

Sodium(4-(4-(pyrazin-2-yl)piperazine-1-carbonyl)phenyl)(quinolin-8-ylsulfonyl)amide(92au)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 8.40 (m, 2H), 8.30 (s, 1H),8.10 (m, 2H), 7.85 (s, 1H), 7.60 (m, 2H), 7.05 (d, 2H), 6.85 (d, 2H),3.50 (bs, 8H); LCMS purity: 98.60%; MS, m/z found 475.15 (M-Na+1)⁺.

N-(4-(4-(pyrazin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamidemethanesulfonate (92av)

¹H NMR (400 MHz, DMSO-d₆) δ:10.45 (s, 1H), 9.05 (d, 1H), 8.52 (d, 1H),8.40 (d, 1H), 8.30 (m, 2H), 8.10 (s, 1H), 7.85 (s, 1H), 7.70 (m, 2H),7.20 (d, 2H), 7.10 (d, 2H), 3.50 (bm, 8H), 2.4 (s, 3H); LCMS purity:98.41%; MS, m/z found 475.15 (M-MsSO₃H+1)⁺.

Synthesis of N4-Aryl/Heteroaryl Piperazine Analogues with SubstitutedPhenyl Central Ring.

General Procedure for Compound 94: Nitrogen was purged through a stirredsolution of arylbromide (93, 2.15 mmol) in 1,4-dioxane (20 ml) at roomtemperature for 30 min. BINAP (0.134 g, 0.215 mmol), palladium acetate(0.0096 g, 0.043 mmol) and cesium carbonate (1.40 g, 4.3 mmol) wereadded to the reaction mixture and the nitrogen purging was continued foranother 20 min. and finally N-Boc piperazine (85, 0.4 g, 2.15 mmol) wasadded and stirred at 100° C. overnight under nitrogen atmosphere. Aftercompletion of the reaction (monitored by TLC), the reaction mixture wasconcentrated under vacuum. The residue was dissolved in water, extractedwith ethyl acetate (3×50 ml). Combined organic extracts were washed withbrine (20 ml), dried over anhydrous Sodium sulfate, filtered andconcentrated under reduced pressure. The crude product was then purifiedby column chromatography (60-120 silica gel) using 10% ethylacetate-hexane to yield compound (94) (40-60%).

General Procedure for Compound (95): N-Boc-N⁴-arylpiperazine (94, 1.075mmol) was taken into a round bottomed flask and was added methanolic-HCl(20 ml, 20%) which resulted in formation of a homogeneous solution andwas stirred for 1 h at room temperature. After completion of thereaction (monitored by TLC), the solvent was removed under vacuum. Thecrude product was washed with ethyl acetate repeatedly and then driedwell to obtain hydrochloride salt (95) (90%) as a white solid.

General Procedure for Compound 97: To a solution of amine (96, 30.16mmol) in a 1:1 mixture of DCM-pyridine (50:50 ml) was addedquinoline-8-sulfonyl chloride (89, 8.24 g, 36.19 mmol) under nitrogenatmosphere. The resultant solution was stirred overnight at roomtemperature. On completion of the reaction (monitored by TLC), thereaction mixture was diluted with dichloromethane (150 ml), washed withwater (3×50 ml), 1N HCl solution (3×50 ml) and brine (50 ml. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. Crude product was co-distilledwith toluene to remove the remnants of pyridine and dried to yieldsulfonamide (97) (70-90%) as an off-white solid and was used as such forthe next step without further purification.

General Procedure for Compounds 98a-1: To a stirred solution of thecarboxylic acid (97, 0.61 mmol) in DMF at 0° C. under nitrogenatmosphere, EDCI (0.129 gm, 0.671 mmol), HOBt (0.91 gm, 0.671 mmol) andDIPEA (0.31 ml, 1.83 mmol) were added and the resultant solution wasstirred at room temperature for 30 min. Amine hydrochloride (95, 0.61mmol) was then added at 0° C. and stirred overnight at room temperature.After completion of the reaction (monitored by TLC), the reactionmixture was poured into 1.0 M HCl and extracted with EtOAc. The organiclayer was washed with saturated NaHCO₃ solution, dried over NaSO4 andfiltered. The solvent was removed by rotary evaporation and the productwas isolated by chromatography on silica gel (60-120 silica gel, 2%MeOH-DCM) or preparative HPLC to yield amide (98a-1) (40-60%) as anoff-white solid.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide-(98a)

¹H NMR (400 MHz, DMSO-d₆) δ:10.30 (s, 1H), 9.10 (d, 1H), 8.52 (d, 1H),8.45 (d, 1H), 8.30 (d, 1H), 7.72 (m, 2H), 6.95 (m, 5H), 6.80 (s, 1H),6.65 (d, 1H), 3.80 (s, 3H), 3.65 (bs, 2H), 3.60 (s, 3H), 3.10 (bs, 2H),2.95 (bs, 2H), 2.80 (bs, 2H); HPLC purity 99.73%; MS, m/z found 533.30(M+1)⁺.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)-3-chlorophenyl)quinoline-8-sulfonamide-(98b)

¹H NMR (400 MHz, DMSO-d₆) δ:10.60 (s, 1H), 9.10 (d, 1H), 8.55 (d, 1H),8.45 (d, 1H), 8.30 (d, 1H), 7.75 (m, 2H), 7.20 (m, 3H), 6.95 (m, 4H),3.80 (s, 3H), 3.70 (bs, 2H), 3.10 (bs, 2H), 2.95 (bs, 2H), 2.80 (bs,2H); HPLC purity 94.42%; MS, m/z found 537.25 (M+1)⁺.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)-2-chlorophenyl)quinoline-8-sulfonamide-(98c)

¹H NMR (400 MHz, DMSO-d₆) δ:10.50 (bs, 1H), 9.10 (d, 1H), 8.58 (d, 1H),8.35 (m, 2H), 7.75 (m, 2H), 7.50 (d, 1H), 7.40 (s, 1H), 7.30 (d, 1H),6.95 (m, 3H), 6.85 (m, 1H), 3.80 (s, 3H), 3.30-3.75 (bm, 4H), 2.95 (bm,4H); LCMS purity 97.99%; MS, m/z found 537.20 (M+1)⁺.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(98d)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.40 (s, 1H), 9.14 (d, 1H), 8.56 (d, 1H),8.30 (d, 1H), 8.25 (d, 1H), 7.70 (m, 2H), 7.15 (s, 1H), 6.90-7.10 (m,4H), 6.83 (m, 2H), 3.75 (s, 3H), 3.30-3.75 (bm, 4H), 2.95 (bm, 4H), 2.05(s, 3H); HPLC purity 99.11%; MS, m/z found 517.14 (M+1)⁺.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)-2-hydroxyphenyl)quinoline-8-sulfonamide(98e)

¹H NMR (400 MHz, DMSO-d₆) δ:10.2 (s, 1H), 9.98 (s, 1H), 9.15 (d, 1H),8.52 (d, 1H), 8.40 (d, 1H), 8.30 (d, 1H), 7.70 (m, 2H), 6.80-6.98 (m,5H), 6.70 (s, 1H), 6.55 (d, 1H), 3.75 (s, 3H), 3.30-3.60 (bm, 4H), 2.85(bm, 4H); HPLC purity 95.25%; MS, m/z found 519.14 (M+1)⁺.

N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(98f)

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (d, 1H), 8.40 (d, 1H), 8.30 (d, 1H),8.05 (d, 1H), 7.80 (t, 1H), 7.60 (m, 2H), 7.13-7.25 (m, 3H), 7.10 (d,1H), 6.95 (m, 3H), 3.90 (s, 3H), 3.65-4.05 (bm, 4H), 3.30 (bm, 4H); LCMSpurity 99.50%; MS, m/z found 521.10 (M+1)⁺.

N-(4-(4-(2-methoxypyridin-3-yl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(98g)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.16 (s, 1H), 8.40-8.51 (d, 1H), 8.20-8.38(m, 2H), 8.02-8.11 (d, 1H), 7.82-8.88 (d, 1H), 7.56-7.66 (m, 2H),7.34-7.38 (m, 2H), 7.02-7.18 (d, 2H), 6.84-6.88 (d, 1H), 4.02 (s, 3H),3.78-3.96 (bs, 2H), 3.58-3.62 (bs, 2H), 2.84-3.12 (bs, 4H), 2.22 (s,3H); HPLC purity 90.41%; MS, m/z found 518.20 (M+1)⁺.

N-(4-(4-(3-methoxypyridin-2-yl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(98h)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.16 (d, 1H), 8.40-8.51 (d, 1H), 8.23-8.31(d, 1H), 8.19 (s, 1H), 8.02-8.11 (d, 1H), 7.82-8.84 (m, 1H), 7.52-7.64(m, 2H), 7.28-7.32 (m, 1H), 7.11-7.18 (s, 1H), 6.98-7.02 (t, 1H),6.82-6.88 (m, 1H), 3.88 (s, 3H), 3.78-3.84 (bs, 2H), 3.26-3.64 (bs, 6H),2.24 (s, 3H); LCMS purity 96.68%, LCMS, m/z found 518.2 (M+1)⁺.

N-(2-fluoro-4-(4-(3-methoxypyridin-2-yl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(98i)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.18 (d, 1H), 8.88 (s, 1H), 8.38-8.42 (d,1H), 8.20-8.28 (m, 2H), 8.02-8.13 (d, 2H), 7.72-7.80 (t, 1H), 7.56-7.62(m, 2H), 6.84-2.12 (dd, 2H), 6.70-6.78 (d, 1H), 3.92 (s, 3H), 3.48-3.82(bs, 4H), 3.00-3.18 (bs, 4H); LCMS purity 96.76%, LCMS, m/z found 522.2(M+1)⁺.

N-(4-(4-(pyridin-4-yl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(98j)

¹H NMR (400 MHz, CDCl₃) δ: 9.10 (d, 1H), 8.45 (d, 1H), 8.30 (m, 4H),8.15 (d, 1H), 7.60 (m, 2H), 7.35 (d, 1H), 7.15 (d, 1H), 7.05 (d, 1H),6.65 (d, 2H), 3.45-3.90 (bm, 4H), 3.30 (bm, 4H), 2.22 (s, 3H); LCMSpurity 100.00%; MS, m/z found 488.30 (M+1)⁺.

N-(4-(4-(2-methoxypyridin-3-yl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(98k)

¹H NMR (400 MHz, CDCl₃) δ: 9.10 (d, 1H), 8.40 (d, 1H), 8.30 (m, 3H),8.05 (d, 1H), 7.80 (m, 1H), 7.60 (m, 2H), 7.05 (d, 1H), 6.95 (d, 1H),6.80 (d, 2H), 3.45-3.90 (bm, 4H), 3.30 (bm, 4H); LCMS purity 99.81%; MS,m/z found 492.30 (M+1)⁺.

N-(4-(4-(2-methoxypyridin-3-yl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(98l)

¹H NMR (400 MHz, CDCl₃) δ: 9.18 (d, 1H), 8.90 (bs, 1H), 8.40 (d, 1H),8.30 (d, 1H), 8.05 (d, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 7.60 (m, 2H),7.05 (m, 1H), 6.95 (d, 1H), 6.80 (m, 1H), 4.00 (s, 3H), 3.45-3.90 (bm,4H), 3.00 (bm, 4H); HPLC purity 96.60%; MS, m/z found 522.25 (M+1)⁺.

Synthesis of N4-Aryl/Heteroaryl Homopiperazine Analogues

General Procedure for Compound (100): Nitrogen was purged through astirred solution of arylbromide (84, 2.15 mmol) in 1,4-dioxane (20 ml)at room temperature for 30 min. BINAP (0.134 g, 0.215 mmol), palladiumacetate (0.0096 g, 0.043 mmol) and cesium carbonate (1.40 g, 4.3 mmol)were added to the reaction mixture and the nitrogen purging wascontinued for another 20 min. and finally N-Boc homopiperazine (99,0.428 g, 2.15 mmol) was added and stirred at 100° C. overnight undernitrogen atmosphere. After completion of the reaction (monitored byTLC), the reaction mixture was concentrated under vacuum. The residuewas dissolved in water, extracted with ethyl acetate (3×50 ml). Combinedorganic extracts were washed with brine (20 ml), dried over anhydrousSodium sulfate, filtered and concentrated under reduced pressure. Thecrude product was then purified by column chromatography (60-120 silicagel) using 10% ethyl acetate-hexane to yield compound (100) (40-50%).

General Procedure for Compound (101): N-Boc-N⁴-arylhomopiperazine (100,1.070 mmol) was taken into a round bottomed flask and was addedmethanolic-HCl (20 ml, 20%) which resulted in formation of a homogeneoussolution and was stirred for 1 h at room temperature. After completionof the reaction (monitored by TLC), the solvent was removed undervacuum. The crude product was washed with ethyl acetate repeatedly andthen dried well to obtain compound (101) (90%) as a white solid.

General Procedure for Compound 103: To a solution of amine (102, 30.16mmol) in a 1:1 mixture of DCM-pyridine (50:50 ml) was addedquinoline-8-sulfonyl chloride (89, 8.24 g, 36.19 mmol) under nitrogenatmosphere. The resultant solution was stirred overnight at roomtemperature. On completion of the reaction (monitored by TLC), thereaction mixture was diluted with dichloromethane (150 ml), washed withwater (3×50 ml), 1N HCl solution (3×50 ml) and brine (50 ml. Thecombined organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. Crude product was co-distilledwith toluene to remove the remnants of pyridine and dried to yieldsulfonamide (103) (70-90%) as an off-white solid and was used as suchfor the next step without further purification.

Procedure for preparation of 4-(quinoline-8-sulfonamido)benzoic acid(104): Ester (103, 5 g, 14.04 mmol) was dissolved in a mixture ofTHF-water (100:100 ml) and maintained at room temperature. To thissolution was added LiOH (3.0 g, 7.0 mmol) and the resultant solution wasrefluxed overnight. The reaction mixture was then washed with ethylacetate (3×50 ml) and then acidified with dilute HCl. The resultantsuspension was filtered and residue was co-distilled with toluene. Thisproduct was then dried under vacuum to yield carboxylic acid (104)(80-90%) as an off-white solid.

General Procedure for Compound 105a-g: To a stirred solution of thecarboxylic acid (104, 0.61 mmol) in DMF at 0° C. under nitrogenatmosphere, EDCI (0.129 gm, 0.671 mmol), HOBt (0.91 gm, 0.671 mmol) andDIPEA (0.31 ml, 1.83 mmol) were added and the resultant solution wasstirred at room temperature for 30 min. Amine hydrochloride (101, 0.61mmol) was then added at 0° C. and stirred overnight at room temperature.After completion of the reaction (monitored by TLC), the reactionmixture was poured into 1.0 M HCl and extracted with EtOAc. The organiclayer was washed with saturated NaHCO₃ solution, dried over NaSO₄ andfiltered. The solvent was removed by rotary evaporation and the productwas isolated by chromatography on silica gel (60-120 silica gel, 2%MeOH-DCM) or preparative HPLC to yield amide (105a-g) (40-60%) as anoff-white solid.

N-(4-(4-phenyl-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(105a)

¹H NMR (400 MHz, DMSO-d₆) δ:10.20 (s, 1H), 9.10 (s, 1H), 8.52 (d, 1H),8.40 (d, 1H), 8.30 (d, 1H), 7.70 (m, 2H), 6.85-7.20 (m, 5H), 6.40-6.75(m, 4H), 3.10-3.70 (m, 8H), 1.82 (bm, 2H); HPLC purity: 95.19%; MS, m/zfound 487.30 (M+1)⁺.

N-(6-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)pyridin-3-yl)quinoline-8-sulfonamide(105b)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.15-9.19 (m, 1H), 8.32-8.42 (m, 2H),8.20-8.26 (d, 1H), 8.10-8.16 (m, 1H), 7.58-7.74 (m, 5H), 7.20-7.28 (m,1H), 6.92-7-18 (m, 2H), 4.15-4.20 (m, 4H), 3.81-3.88 (m, 4H), 3.82 (s,3H), 2.42-2.58 (m, 2H); LCMS purity 99.92%; MS, m/z found 518.5 (M+1)⁺.

N-(2-chloro-4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide-(105c)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.15 (d, 1H), 8080-8.92 (m, 1H), 8.40-8.52(m, 1H), 8.20-8.26 (d, 1H), 8.02-8.06 (d, 1H), 7.68-7.82 (dd, 1H),7.54-7.62 (m, 2H), 6.84-7.05 (m, 5H), 6.66-6.68 (d, 1H), 3.82 (s, 3H),3.74-3.78 (m, 2H), 3.41-3.54 (m, 2H), 3.21-3.36 (m, 3H), 3.16-3.19 (bs,3H), 2.00-2.11 (bs, 1H), 1.82-1.98 (bs, 1H); LCMS purity 97.10%; LCMS,m/z found 551.4 (M+1)⁺.

N-(3-chloro-4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide-(105d)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.15 (s, 1H), 8.32-8.44 (m, 3H), 8.05-8.10(m, 1H), 7.60-7.72 (m, 2H), 7.22-7.32 (m, 2H), 7.12 (s, 1H), 6.88-7.05(m, 3H), 6.80-6.84 (m, 1H), 3.74-3.91 (m, 2H), 3.41 (s, 3H), 3.14-3.42(m, 6H), 1.82-1.86 (m, 2H); LCMS purity 99.47%; MS, m/z found 551.4(M+1)⁺.

N-(2-fluoro-4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(105e)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.15 (s, 1H), 8.32-8.44 (d, 2H), 8.02-8.07(t, 1H), 7.70-7.84 (m, 1H), 7.51-7.62 (m, 3H), 7.37-7-40 (m, 2H),6.82-7.10 (m, 4H), 3.91-4.15 (m, 2H), 3.78-3.88 (m, 2H), 3.82 (s, 3H),3.62-3.70 (m, 2H), 3.52-3.58 (m, 2H), 2.35-42 (m, 2H); LCMS purity99.01%; MS, m/z found 535.5 (M+1)⁺.

N-(4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide-(105f)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.25 (s, 1H), 9.10 (d, 1H), 8.54-8.58 (d,1H), 8.22-8.30 (dd, 2H), 7.68-7.76 (m, 2H), 6.78-7.18 (m, 7H), 3.81 (s,3H), 3.20-3.64 (m, 8H), 2.15 (s, 3H), 1.82 (bm, 2H); LCMS purity:99.67%; MS, m/z found 531.4 (M+1)⁺.

N-(2-methoxy-4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(105g)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.17 (d, 1H), 8.44 (s, 1H), 8.34-8.58 (dd,2H), 8.02-8.10 (d, 1H), 7.56-7.64 (t, 2H), 6.82-6.94 (m, 4H), 6.66-6.68(m, 1H), 6.24-6.38 (m, 1H), 3.81 (s, 3H), 3.64 (s, 3H), 3.58-3.60 (m,2H), 3.24-3.40 (m, 4H), 3.04-3.22 (m, 2H), 1.82 (bm, 2H); LCMS purity:94.21%; MS, m/z found 547.3 (M+1)⁺.

Synthesis of N4-Aryl/Heteroaryl Piperazine/Homopiperazine ReverseSulfonamide Analogues

General Procedure for Compound (108): Nitrogen was purged through astirred solution of arylbromide (106, 0.4 g, 2.15 mmol) in 1,4-dioxane(20 ml) at room temperature for 30 min.

BINAP (0.134 g, 0.215 mmol), palladium acetate (0.0096 g, 0.043 mmol)and cesium carbonate (1.40 g, 4.3 mmol) were added to the reactionmixture and the nitrogen purging was continued for another 20 min. andfinally N-Boc amine (107, 2.15 mmol) was added and stirred at 100° C.overnight under nitrogen atmosphere. After completion of the reaction(monitored by TLC), the reaction mixture was concentrated under vacuum.The residue was dissolved in water, extracted with ethyl acetate (3×50ml). Combined organic extracts were washed with brine (20 ml), driedover anhydrous Sodium sulfate, filtered and concentrated under reducedpressure. The crude product was then purified by column chromatography(60-120 silica gel) using 10% ethyl acetate-hexane to yield compound(108) (40-60%).

General Procedure for Compound (109): Compound 108 (1.075 mmol) wastaken into a round bottomed flask and was added methanolic-HCl (20 ml,20%) which resulted in formation of a homogeneous solution and wasstirred for 1 h at room temperature. After completion of the reaction(monitored by TLC), the solvent was removed under vacuum. The crudeproduct was washed with ethyl acetate repeatedly and then dried well toobtain compound (109) (90%) as a white solid.

General Procedure for Compound 112: To a solution of(4-chlorosulfonyl)benzoic acid (110, 1.6 g, 7.27 mmol) in a 1:1 mixtureof DCM-pyridine (50:50 ml) was added 8-aminoquinoline (111, 1.15 g, 8.0mmol) under nitrogen atmosphere. The resultant solution was stirredovernight at room temperature. On completion of the reaction (monitoredby TLC), the reaction mixture was diluted with dichloromethane (150 ml),washed with water (3×50 ml), 1N HCl solution (3×50 ml) and brine (50 ml.The combined organic extracts were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. Crude product was co-distilledwith toluene to remove the remnants of pyridine and dried to yieldsulfonamide (112) (1.9 g, 80%) as an off-white solid and was used assuch for the next step without further purification.

General Procedure for Compound 113/114: To a stirred solution of thecarboxylic acid (112, 0.61 mmol) in DMF at 0° C. under nitrogenatmosphere, EDCI (0.129 gm, 0.671 mmol), HOBt (0.91 gm, 0.671 mmol) andDIPEA (0.31 ml, 1.83 mmol) were added and the resultant solution wasstirred at room temperature for 30 min. Amine hydrochloride (109, 0.61mmol) was then added at 0° C. and stirred overnight at room temperature.After completion of the reaction (monitored by TLC), the reactionmixture was poured into 1.0 M HCl and extracted with EtOAc. The organiclayer was washed with saturated NaHCO₃ solution, dried over NaSO₄ andfiltered. The solvent was removed by rotary evaporation and the productwas isolated by chromatography on silica gel (60-120 silica gel, 2%MeOH-DCM) or preparative HPLC to yield amide (113/114) (50-60%) as anoff-white solid.

4-(4-(2-methoxyphenyl)piperazine-1-carbonyl)-N-(quinolin-8-yl)benzenesulfonamide(113)

¹H NMR (400 MHz, DMSO-d₆) δ: 10.18 (s, 1H), 8.92 (s, 1H), 8.54-8.56 (d,1H), 7.89-7.93 (d, 2H), 7.66-7.94 (m, 2H), 7.44-7.57 (m, 4H), 6.94-6.98(m, 2H), 6.83-6.86 (m, 2H), 3.78 (s, 3H), 3.61-3.69 (m, 2H), 3.20-3.54(m, 2H), 2.91-2.94 (bs, 2H), 1.82-1.86 (bs, 2H); HPLC purity 99.01%; MS,m/z found 503.3 (M+1)⁺.

4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbonyl)-N-(quinolin-8-yl)benzenesulfonamide(114)

¹H NMR (400 MHz, DMSO-d₆) δ: 9.25 (s, 1H), 8.78 (s, 1H), 8.15 (d, 1H),7.80-7.99 (m, 3H), 7.38-7.59 (m, 4H), 7.15-7.27 (m, 2H), 6.80-7.00 (m,3H), 3.74-3.91 (m, 2H), 3.41 (s, 3H), 3.14-3.42 (m, 6H), 1.82-1.86 (m,2H); LCMS purity 99.97%; MS, m/z found 517.3 (M+1)⁺.

Synthesis of Piperazine Based Compounds with Substituted Phenyl Rings

Ethyl 4-(quinoline-8-sulfonamido)benzoate (90): To a stirred solution ofethyl 4-aminobenzoate (5 gm, 30.3 mmol) under nitrogen atmosphere wasadded pyridine (50 ml) at 0° C. and stirred for 10 min.Quinoline-8-sulfonyl chloride 89 (8.94 gm, 39.4 mmol) was then added tothe reaction mixture at the same temperature. The resulting mixture wasstirred for 16 hr at RT. After completion of the reaction, the solventwas removed under low pressure. The traces of pyridine were removed byco-distillation with toluene. Diethylether was added to the resultingresidue, and the solid product was filtered out and air-dried. Theresulting crude product (8.0 gm, 74%) was taken to the next step withoutfurther purification.

4-(Quinoline-8-sulfonamido)benzoic acid (91): To a stirred solution ofethyl 4-(quinoline-8-sulfonamido)benzoate 90 (8 gm, 22.4 mmol) inTHF:H₂O (1:1) under nitrogen atmosphere was added solid LiGH (9.4 gm,224 mmol) at RT. The solution was then refluxed for 6 hr. Aftercompletion of the reaction, the reaction mixture was washed with ethylacetate (2×100 ml) to remove non polar impurities. The aqueous layer wasacidified (pH 4) with citric acid solution. The resultant precipitatewas filtered out and air-dried. The traces of water were removed byco-distillation with toluene. The resultant off white solid (5.9 gm,80%) was taken to the next step without further purification.

N-(4-(Piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide (115): EDCI(3.8 g, 19.8 mmol) and HOBT (2.67 g, 19.8 mmol) were added to a stirredsolution of the acid 91 (6.5 g, 19.8 mmol) in anhydrous DMF. Thetemperature of the mixture was reduced to 0° C., at which time DIPEA (11ml, 59.45 mmol) was added under nitrogen atmosphere and the resultantsolution (or suspension) was stirred at room temperature for 30 min.Boc-piperazine (3.68 g, 19.8 mmol) was then added at 0° C. The reactionmixture was then brought to room temperature and stirred overnight.After completion of the reaction, the reaction mixture was diluted withwater and extracted with ethyl acetate (3×70 ml). The organic layer waswashed with water (3×50 ml), dried over anhydrous sodium sulfate,filtered and concentrated over the rotary evaporator to get the crudeproduct. Crude product was purified by column chromatography (60-120silica gel, 2% MeOH-DCM) to get pure product, Boc-115 (8.0 g, 82%) as anoff-white solid, which was subjected to the treatment with methanolicHCl (100 ml) for 2 hr at RT. After the complete cleavage of Boc-group,the solvent was removed under low pressure, to give the crude product asan HCl salt. The aqueous solution of the salt was washed withdiethylether and basified with NaHCO₃ (pH 10). The desired product wasthen partitioned into ethyl acetate, dried with anhydrous Na₂SO₄ and thesolvent removed under low pressure to get the free amine 115 as offwhite solid (6.0 g, 95%).

General procedure for the synthesis of amides 116a-bg: EDCI (48 mg,0.2525 mmol) and HOBT (34 mg, 0.2525 mmol) were added to a stirredsolution of the Ar—COOH (0.2525 mmol) in anhydrous DMF. The temperatureof the mixture was reduced to 0° C., at which time DIPEA (139 μl, 0.7575mmol) was added under nitrogen atmosphere and the resultant solution (orsuspension) was stirred at room temperature for 30 min. Amine 115 (100mg, 0.2525 mmol) was then added at 0° C. The reaction mixture was thenbrought to room temperature and stirred overnight. After completion ofthe reaction, the reaction mixture was diluted with water and extractedwith ethyl acetate (3×15 ml). The organic layer was washed with water(3×10 ml), dried over anhydrous sodium sulfate, filtered andconcentrated over the rotary evaporator to get the crude product. Crudeproduct was purified by either by silica column chromatography orpreparative HPLC to obtain the pure products in 55-69% yields.

N-(4-(4-Picolinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116a)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.4-7.6(m, 2H), 7.7 (m, 2H), 7.9 (m, 1H), 8.3 (m, 1H), 8.4-8.6 (m, 3H), 9.1 (d,1H), 10.2-10.4 (s, 1H); HPLC Purity: 95.7%; LCMS, m/z found 502.1(M+1)⁺.

N-(4-(4-Nicotinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116b)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.4 (m,1H), 7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.3 (m, 2H), 8.4-8.6 (m, 3H), 9.1 (d,1H), 10.2-10.4 (s, 1H); HPLC Purity: 96.7%; LCMS, m/z found 502.2(M+1)⁺.

N-(4-(4-Isonicotinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116c)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6 (m,2H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.6 (m, 3H), 9.1 (m, 2H), 10.2-10.4(s, 1H); HPLC Purity: 98.8%; LCMS, m/z found 502.1 (M+1)⁺.

N-(4-(4-(2-Methylnicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116d)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2 (s, 3H), 3.3-3.8 (m, 8H), 7.0-7.2 (m,4H), 7.4 (m, 1H), 7.6-7.9 (m, 3H), 8.2 (m, 1H), 8.4-8.6 (m, 3H), 9.1 (m,1H), 10.4 (s, 1H); HPLC Purity: 99.2%; LCMS, m/z found 516.4 (M+1)⁺.

N-(4-(4-(2,6-Dichloronicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116e)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2 (s, 3H), 3.3-3.8 (m, 8H), 7.0-7.4 (m,4H), 7.6 (m, 3H), 8.0 (m, 1H), 8.2 (m, 2H), 8.6 (m, 1H), 9.1 (m, 1H),10.4 (s, 1H); HPLC Purity: 98.8%; LCMS, m/z found 570.3 (M+1)⁺.

N-(4-(4-(6-Methylpicolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116f)

¹H NMR (400 MHz, DMSO-d₆) δ:2.5 (s, 3H), 3.3-3.8 (m, 8H), 7.0-7.3 (m,5H), 7.4 (m, 1H), 7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 1H), 8.6 (m,1H), 10.4 (s, 1H); HPLC Purity: 99.9%; LCMS, m/z found 516.1 (M+1)⁺.

N-(4-(4-(Pyrazine-2-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116g)

¹H NMR (400 MHz, CDCl₃) δ: 3.3-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6 (m,2H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.2-8.4 (m, 1H), 8.6 (m, 2H), 9.0 (s,1H), 9.2 (m, 1H); HPLC Purity: 97.5%; LCMS, m/z found 503.2 (M+1)⁺.

N-(4-(4-(3-Methoxybenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116h)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.3-3.8 (m, 8H), 3.9 (s, 3H), 6.9-7.0 (m,3H), 7.2 (m, 4H), 7.4 (m, 1H), 7.9 (m, 2H), 8.2 (m, 1H), 8.4-8.6 (m,2H), 9.1 (s, 1H), 10.5 (s, 1H); HPLC Purity: 97.3%; LCMS, m/z found531.3 (M+1)⁺.

N-(4-(4-(2-Fluorobenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116i)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2 (m, 4H), 3.4 (m, 2H), 3.6 (m, 2H)7.0-7.5 (m, 8H), 7.7 (m, 2H), 8.2 (m, 1H), 8.4-8.6 (m, 2H), 9.1 (m, 1H),10.5 (s, 1H); HPLC Purity: 97.3%; LCMS, m/z found 519.3 (M+1)⁺.

N-(4-(4-(3-Fluorobenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116j)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 6H), 7.4 (m,2H), 7.8 (m, 2H), 8.2-8.5 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H); HPLCPurity: 97.3%; LCMS, m/z found 519.3 (M+1)⁺.

N-(4-(4-(4-Fluorobenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116k)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 6H), 7.4 (m,2H), 7.8 (m, 2H), 8.2-8.5 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H); HPLCPurity: 97.3%; LCMS, m/z found 519.3 (M+1)⁺.

N-(4-(4-(2,3-Difluorobenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116l)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2 (m, 4H), 3.6 (m, 4H), 7.0-7.4 (m, 6H),7.5-7.8 (m, 3H), 8.2 (m, 1H), 8.4-8.6 (m, 2H), 9.1 (m, 1H), 10.5 (s,1H); HPLC Purity: 94.3%; LCMS, m/z found 537.3 (M+1)⁺.

N-(4-(4-(2,3-Dimethoxybenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116m)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2 (m, 4H), 3.6 (m, 4H), 3.7 (s, 3H), 3.8(s, 3H), 6.8 (m, 1H), 7.0-7.2 (m, 6H), 7.6-7.8 (m, 2H), 8.2 (m, 1H),8.4-8.6 (m, 2H) 9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity: 97.2%; LCMS, m/zfound 561.1 (M+1)⁺.

N-(4-(4-Benzoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116n)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (s, 8H), 6.8 (m, 1H), 7.0-7.2 (m,6H), 7.6-7.8 (m, 2H), 8.2 (m, 2H), 8.4-8.6 (m, 2H), 9.1 (m, 1H), 10.5(s, 1H); HPLC Purity: 98.2%; LCMS, m/z found 501.2 (M+1)⁺.

N-(4-(4-(4-Chlorobenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116o)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.2-7.6(m, 4H), 7.6-7.8 (m, 2H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H);HPLC Purity: 99.7%; LCMS, m/z found 535.0 (M+1)⁺.

N-(4-(4-(4-Chloro-2,5-difluorobenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116p)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6-7.8(m, 4H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity: 99.7%;LCMS, m/z found 555.4 (M+1)⁺.

N-(4-(4-(2-Naphthoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116r)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.4-7.6 (m,5H), 7.8 (m, 4H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 9.1 (m, 1H), 10.5 (s,1H); HPLC Purity: 98.4%; LCMS, m/z found 551.4 (M+1)⁺.

N-(4-(4-(2-(4-Fluorophenyl)-2-methylpropanoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116s)

¹H NMR (400 MHz, DMSO-d₆) δ:1.2 (s, 6H), 3.2-3.8 (m, 8H), 7.0-7.2 (m,8H), 7.6-7.8 (m, 2H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H); HPLCPurity: 98.4%; LCMS, m/z found 561.4 (M+1)⁺.

N-(4-(4-(2-Methyl-2-phenylpropanoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116t)

¹H NMR (400 MHz, CD₃OD) δ: 3.2-3.8 (m, 8H), 3.9 (s, 2H), 7.2-7.4 (m,9H), 7.6-7.8 (m, 2H), 8.2 (m, 1H), 8.4 (m, 2H), 9.1 (m, 1H), 10.5 (s,1H); HPLC Purity: 99.4%; LCMS, m/z found 515.3 (M+1)⁺.

N-(4-(4-(3-(Thiophen-2-yl)propanoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116u)

¹H NMR (400 MHz, DMSO-d₆) δ:2.4-2.6 (m, 3H), 2.7 (m, 2H), 3.0 (m, 2H),3.2-3.6 (m, 5H), 6.9 (m, 2H), 7.0-7.2 (m, 4H), 7.4 (m, 1H), 7.8 (m, 2H),8.2-8.6 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity: 98.0%; LCMS,m/z found 535.1 (M+1)⁺.

N-(4-(4-(2-Cyclopropylacetyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116v)

¹H NMR (400 MHz, CDCl₃) δ:0.2 (m, 2H), 0.6 (m, 2H), 1.0 (m, 1H), 3.3-3.8(m, 8H), 7.0-7.2 (m, 4H), 7.6 (m, 2H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 9.1(m, 1H), 10.5 (s, 1H); HPLC Purity: 99.9%; LCMS, m/z found 479.4 (M+1)⁺.

N-(4-(4-(Thiazole-4-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116w)

¹H NMR (400 MHz, CDCl₃) δ: 3.3-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6-7.8 (m,2H), 8.0-8.2 (m, 2H), 8.4-8.6 (m, 2H), 9.1 (m, 2H), 10.5 (s, 1H); HPLCPurity: 98.2%; LCMS, m/z found 508.1 (M+1)⁺.

N-(4-(4-(1,2,3-Thiadiazole-4-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116x)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.3-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6-7.8(m, 2H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), 9.6 (s, 1H), 10.5 (s, 1H); HPLCPurity: 98.2%; LCMS, m/z found 508.1 (M+1)⁺.

N-(4-(4-(1H-Pyrrole-2-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116y)

¹H NMR (400 MHz, DMSO-d₆) δ:3.2-3.8 (m, 8H), 6.0 (m, 1H), 6.4 (m, 1H),6.8 (m, 1H), 7.0-7.2 (m, 4H), 7.6-7.8 (m, 2H), 8.2 (m, 1H), 8.4-8.6 (m,2H), 9.1 (m, 1H), 10.5 (s, 1H), 11.4 (s, 1H); HPLC Purity: 99.2%; LCMS,m/z found 490.3 (M+1)⁺.

N-(4-(4-(2-Methylthiazole-5-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116z)

¹H NMR (400 MHz, CDCl₃) δ:2.3 (s, 3H), 3.6-3.8 (m, 8H), 7.0-7.2 (m, 5H),7.6 (m, 2H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 9.1 (m, 1H); HPLC Purity:99.7%; LCMS, m/z found 521.6 (M+1)⁺.

N-(4-(4-(Cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116aa)

¹H NMR (400 MHz, DMSO-d₆) δ: 0.6-0.8 (m, 2H), 2.0 (m, 1H), 3.2-3.8 (m,8H), 7.0-7.2 (m, 4H), 7.6-7.8 (m, 2H), 8.2 (m, 1H), 8.4-8.6 (m, 2H), 9.1(m, 1H), 10.5 (s, 1H); HPLC Purity: 99.0%; LCMS, m/z found 465.35(M+1)⁺.

N-(4-(4-(Cyclohexanecarbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116ab)

¹H NMR (400 MHz, DMSO-d₆) δ:1.0-1.2 (m, 5H), 1.6-1.8 (m, 5H), 2.5 (m,1H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6-7.8 (m, 2H), 8.2 (m, 1H),8.4-8.6 (m, 2H), 9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity: 93.0%; LCMS,m/z found 507.15 (M+1)⁺.

N-Phenyl-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ac)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 6H), 7.4 (m,2H), 7.6 (m, 2H), 8.2 (m, 2H), 8.4-8.6 (m, 2H), 9.1 (m, 1H), 10.5 (s,1H); HPLC Purity: 99.4%; LCMS, m/z found 516.4 (M+1)⁺.

N-(3-Methoxyphenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ad)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.8 (m 8H), 3.9 (s, 3H), 6.48 (s, 1H), 7.23(m, 7H), 7.9 (m, 2H), 8.3 (s, 1H), 8.4-8.6 (d, 2H), 8.72 (s, 1H), 9.24(s, 1H), 10.53 (s, 1H); HPLC Purity: 95.27%; MS, m/z found 546.16(M+1)⁺.

N-(2-Methoxyphenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ae)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.8 (m 8H), 3.9 (s, 3H), 6.8 (d 2H), 6.98(d, 2H), 7.23 (m, 4H), 7.9 (m, 4H), 8.42 (d, 1H), 8.6 (d, 1H), 8.72 (d,1H), 9.24 (s, 1H), 10.53 (s, 1H); HPLC Purity: 97.73%; MS, m/z found546.14 (M+1)⁺.

N-(4-Methoxyphenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116af)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.8 (m 8H), 3.9 (s, 3H), 5.9 (S 1H), 6.8 (d2H), 6.98 (d, 2H), 7.23 (m, 6H), 7.9 (m, 2H), 8.2-8.6 (m, 4H), 9.24 (s,1H), 10.53 (s, 1H); HPLC Purity: 98.22%; MS, m/z found 546.17 (M+1)⁺.

N-(2,4-Difluorophenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ag)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.4 (m 8H), 7.9 (m 7H), 7.5 (m, 2H),8.2-8.5 (d, 3H), 9.24 (s, 1H); HPLC Purity: 95.79%; MS, m/z found 552.19(M+1)⁺.

N-(2-Fluorophenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ah)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.8 (m 8H), 7.2 (m, 7H), 7.6 (S, 1H), 7.9(d, 2H), 8.2-8.6 (d, 4H), 9.24 (s, 1H), 10.53 (s, 1H); HPLC Purity:95.38%; MS, m/z found 534.22 (M+1)⁺.

N-(4-Fluorophenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ai)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.8 (m 8H), 7.2 (m, 5H), 7.42 (d, 2H), 7.6(d, 2H), 8.2-8.6 (d, 4H), 10.53 (s, 1H), 9.24 (s, 1H); HPLC Purity:98.92%; MS, m/z found 532.42 (M+1)⁺.

N-(4-Cyanophenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116aj)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.8 (m 8H), 7.23 (d, 4H), 7.9 (m, 6H), 8.42(d, 1H), 8.2 (d, 1H), 8.15 (d, 1H), 9.23 (S 1H),), 9.1 (s, 1H), 10.53(s, 1H); HPLC Purity: 97.97%; MS, m/z found 541.30 (M+1)⁺.

N-(2-Chlorophenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ak)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.3 (m 8H), 7.2 (m, 6H), 7.3 (d, 4H), 7.9(m, 2H), 8.42 (d, 2H), 8.5 (d, 1H), 8.52 (d, 1H), 9.24 (s, 1H), 10.53(s, 1H); HPLC Purity: 97.73%; MS, m/z found 546.14 (M+1)⁺.

4-(4-(Quinoline-8-sulfonamido)benzoyl)-N-(p-tolyl)piperazine-1-carboxamide(116al)

¹H NMR (400 MHz, DMSO-d₆) δ:2.2 (S 3H), 3.8 (m 8H), 7.1-7.3 (m, 7H), 7.9(m, 2H), 8.23-8.4 (d, 4H), 9.1 (s, 1H), 10.53 (s, 1H); HPLC Purity:98.27%; MS, m/z found 530.19 (M+1)⁺.

N-(4-Chlorophenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116am)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.3 (m 8H), 7.2 (m, 6H), 7.4 (d, 2H), 7.9(m, 2H), 8.42 (d, 2H), 8.5 (d, 1H), 8.62 (d, 1H), 9.24 (s, 1H), 10.43(s, 1H); HPLC Purity: 97.92%; MS, m/z found 550.14 (M+1)⁺.

4-(4-(Quinoline-8-sulfonamido)benzoyl)-N-(4-(trifluoromethyl)phenyl)piperazine-1-carboxamide(116an)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.3 (m 8H), 7.4 (m, 6H), 7.5 (d, 2H), 8.0(m, 2H), 8.6 (d, 2H), 8.7 (d, 1H), 8.8 (d, 1H), 9.24 (s, 1H), 10.43 (s,1H); HPLC Purity: 97.90%; MS, m/z found 584.05 (M+1)⁺.

N-(2-Chloro-5-(trifluoromethyl)phenyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carbothioamide(116ao)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6-7.8(m, 5H), 8.2 (m, 1H), 8.4-8.6 (m, 2H), 9.1 (m, 1H), 9.4 (m, 1H), 10.5(s, 1H); HPLC Purity: 96.1%; LCMS, m/z found 634.17 (M+1)⁺.

Ethyl4-(4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamido)butanoate(116ap)

¹H NMR (400 MHz, CDCl₃) δ:1.2 (t, 3H), 1.8 (q, 2H), 2.4 (t, 2H), 3.2-3.8(m, 8H), 3.6 (m, 2H), 4.1 (m, 2H), 5.0 (m, 1H), 7.0-7.2 (m, 4H), 7.6 (m,2H), 8.0 (m, 1H), 8.4 (m, 2H), 8.6 (m, 1H), 9.1 (m, 1H); HPLC Purity:98.7%; LCMS, m/z found 554.19 (M+1)⁺.

Ethyl3-(4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamido)propanoate(116aq)

¹H NMR (400 MHz, CD₃OD) δ:1.2 (t, 3H), 2.5 (t, 2H), 3.2-3.8 (m, 8H), 3.6(m, 2H), 4.1 (m, 2H), 7.2 (m, 4H), 7.6 (m, 2H), 8.2 (m, 1H), 8.4 (m,2H), 9.1 (m, 1H); HPLC Purity: 99.3%; LCMS, m/z found 540.1 (M+1)⁺.

N-(3-Chloropropyl)-4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxamide(116ar)

¹H NMR (400 MHz, CD₃OD) δ: 2.5 (m, 2H), 3.6 (t, 2H), 3.8 (t, 3H),3.2-3.8 (m, 8H), 7.2 (m, 4H), 7.6 (m, 2H), 8.2 (m, 1H), 8.4 (m, 2H), 9.1(m, 1H); HPLC Purity: 98.3%; LCMS, m/z found 517.1 (M+1)⁺.

N-(4-(4-(3-(4-(Trifluoromethyl)phenyl)propanoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(116as)

¹H NMR (400 MHz, DMSO-d₆) δ:2.7 (t, 2H), 2.9 (t, 2H), 3.2-3.8 (m, 8H),7.2 (m, 4H), 7.5 (m, 2H), 7.6-7.8 (m, 4H), 8.3 (m, 1H), 8.4-8.6 (m, 2H),9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity: 99.0%; LCMS, m/z found 597.45(M+1)⁺.

Isobutyl 4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(116at)

¹H NMR (400 MHz, DMSO-d₆) δ:0.8-0.91 (t, 6H), 1.90 (m, 1H), 3.4-3.6 (m,8H), 3.8 (d, 2H), 7.0-7.2 (m, 4H), 7.6-7.8 (m, 2H), 8.2 (m, 1H), 8.4-8.6(m, 2H), 9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity: 99.91%; LCMS, m/z found497.18 (M+1)⁺.

Ethyl 4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(116au)

¹H NMR (400 MHz, DMSO-d₆) δ:1.3 (t, 3H), 3.4-3.6 (m, 8H), 4.1 (q, 2H),7.2 (m, 4H), 7.7-7.8 (m, 2H), 8.2 (m, 1H), 8.5-8.6 (m, 2H), 9.2 (m, 1H),10.4 (s, 1H); HPLC Purity: 99.65%; LCMS, m/z found 469.10 (M+1)⁺.

Isopropyl 4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(116av)

¹H NMR (400 MHz, DMSO-d₆) δ:1.02-1-21. (m, 6H), 4.81-4.9 (m, 1H),7.0-7.2 (m, 4H), 7.6-7.8 (m, 2H), 8.2 (m, 1H), 8.4-8.6 (m, 2H), 9.1 (m,1H), 10.5 (s, 1H); HPLC Purity: 94.12%; LCMS, m/z found 481.51 (M-1)⁺.

Phenyl 4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(116aw)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.4-3.8 (m, 8H), 7.0-7.2 (m, 7H), 7.4-7.6(m, 2H), 7.8.-7.85 (m, 2H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H);HPLC Purity: 99.71%; LCMS, m/z found 517.25 (M+1)⁺.

3-Fluorophenyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116ax)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.4-3.8. (m, 8H), 7.0-7.2 (m, 7H), 7.4-7.6(m, 1H), 7.8.-7.85 (m, 2H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H);HPLC Purity: 95.75%; LCMS, m/z found 535.25 (M+1)⁺.

4-Fluorophenyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116ay)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.4-3.8 (m, 8H), 7.0-7.2 (m, 8H), 7.8-7.85(m, 2H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity:95.05%; LCMS, m/z found 535.27 (M+1)⁺.

4-Chlorophenyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116az)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.4-3.8 (m, 8H), 7.0-7.2 (m, 6H), 7.4 (d,2H), 7.7 (m, 2H), 8.3-8.5 (m, 3H), 9.2 (m, 1H), 10.5 (s, 1H); HPLCPurity: 99.41%; LCMS, m/z found 549.56 (M)⁺.

p-Tolyl 4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(116ba)

¹H NMR (400 MHz, DMSO-d₆) δ:2.2 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 2H),7.2 (m, 6H), 7.6-7.8 (m, 2H), 8.3 (m, 1H), 8.4-8.6 (m, 2H), 9.1 (m, 1H),10.5 (s, 1H); HPLC Purity: 99.5%; LCMS, m/z found 531.58 (M+1)⁺.

3-Chlorophenyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116bb)

¹H NMR (400 MHz, DMSO-d₆) δ:3.4-3.8 (m, 8H), 7.0-7.2 (m, 8H), 7.6-7.8(m, 2H), 8.2-8.6 (m, 3H), 9.1 (m, 1H), HPLC Purity: 99.79%; LCMS, m/zfound 549.58 (M)⁺.

m-Tolyl 4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(116bc)

¹H NMR (400 MHz, DMSO-d₆) δ: 2.23-2.4 (t, 3H), 3.4-3.8. (t, 8H),6.82-6.98 (m, 6H), 7.0-7.2 (m, 6H), 7.6-7.8 (m, 2H), 8.2-8.6 (m, 3H),9.1 (m, 1H); HPLC Purity: 99.26%; LCMS, m/z found 531.16 (M+1)⁺.

(S)-Tetrahydrofuran-3-yl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116bd)

¹H NMR (400 MHz, DMSO-d₆) δ: 2.23-2.4 (m, 2H), 2.6-2.98 (m, 4H), 3.4-3.8(t, 8H), 3.8-3.95 (m, 4H), 5.23-5.35 (m, 1H), 7.0-7.2 (m, 4H), 7.6-7.8(m, 2H), 8.0-8.1 (d, 2H), 8.32-8.45 (dd, 2H), 9.1 (m, H); HPLC Purity:96.89%; LCMS, m/z found 533.05 (M+23)⁺.

(Tetrahydrofuran-2-yl)methyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116be)

¹H NMR (400 MHz, DMSO-d₆) δ: 2.23-2.4 (m, 3H), 3.4-3.8 (t, 8H), 3.8-3.95(m, 4H), 7.0-7.2 (m, 4H), 7.6-7.8 (m, 2H), 8.0-8.1 (d, 2H), 8.32-8.45(dd, 3H), 9.1 (m, 1H); HPLC Purity: 99.84%; LCMS, m/z found 525.10(M+1)⁺.

2-Cyclopentylethyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116bf)

¹H NMR (400 MHz, DMSO-d₆) δ:1.2-1.32 (d, 4H), 2.0-2.12 (m, 8H), 3.4-3.8(t, 8H), 4.62-4.72 (m, 1H), 7.0-7.2 (m, 6H), 7.6-7.8 (m, 2H), 8.0-8.1(d, 2H), 8.32-8.45 (dd, 3H), 9.1 (m, 1H); HPLC Purity: 99.89%; LCMS, m/zfound 537.10 (M+1)⁺.

2-Cyclohexylethyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (116bg)

¹H NMR (400 MHz, CDCl₃) δ: 1.0 (m, 2H), 1.2 (m, 7H), 1.5 (m, 1H), 1.6(m, 5H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H), 7.6-7.8 (m, 2H), 8.0 (m, 1H),8.2-8.4 (m, 2H), 8.6 (m, 2H), 9.1 (m, 1H); HPLC Purity: 99.6%; LCMS, m/zfound 551.45 (M+1)⁺.

Synthesis of Piperazine Derivatives with 3-methyl, 2-methyl, 3-fluoro,3-chloro, 3-hydroxy or 3-methoxy Substituted Phenyl Rings

General procedure for the synthesis of sulfonamide 118: To a stirredsolution of amine 7 (30.3 mmol) under nitrogen atmosphere was addedpyridine (50 ml) at 0° C. and stirred for 10 min. Quinoline-8-sulfonylchloride 89 (8.94 gm, 39.4 mmol) was then added to the reaction mixtureat the same temperature. The resulting mixture was stirred for 16 hr atRT. After completion of the reaction, the solvent was removed under lowpressure. The traces of pyridine were removed by co-distillation withtoluene. Diethylether was added to the resulting residue, and the solidproduct was filtered out and air-dried. The resulting crude product (8.0gm, 74%) was then to the next step without further purification.

General procedure for the synthesis of sulfonamide 119: EDCI (3.8 g,19.8 mmol) and HOBT (2.67 g, 19.8 mmol) were added to a stirred solutionof the acid 118 (19.8 mmol) in anhydrous DMF. The temperature of themixture was reduced to 0° C., at which time DIPEA (11 ml, 59.45 mmol)was added under nitrogen atmosphere and the resultant solution (orsuspension) was stirred at room temperature for 30 min. Boc-piperazine(3.68 g, 19.8 mmol) was then added at 0° C. The reaction mixture wasthen brought to room temperature and stirred overnight. After completionof the reaction, the reaction mixture was diluted with water andextracted with ethyl acetate (3×70 ml). The organic layer was washedwith water (3×50 ml), dried over anhydrous sodium sulfate, filtered andconcentrated over the rotary evaporator to get the crude product.

Crude product was purified by column chromatography (60-120 silica gel,2% MeOH-DCM) to get pure product, Boc-119 (81%) as an off-white solid,which was subjected to the treatment with methanolic HCl (100 ml) for 2hr at RT. After the complete cleavage of Boc-group, the solvent wasremoved under low pressure, to give the crude product as an HCl salt.The aqueous solution of the salt was washed with diethylether andbasified with NaHCO₃ (pH 10). The desired product was then partitionedinto ethyl acetate, dried with anhydrous Na₂SO₄ and the solvent removedunder low pressure to get the free amine 119 as off white solid (95%).

General procedure for the synthesis of amides 120a-cu: EDCI (48 mg,0.2525 mmol) and HOBT (34 mg, 0.2525 mmol) were added to a stirredsolution of the Ar—COOH (0.2525 mmol) in anhydrous DMF. The temperatureof the mixture was reduced to 0° C., at which time DIPEA (139 μl, 0.7575mmol) was added under nitrogen atmosphere and the resultant solution (orsuspension) was stirred at room temperature for 30 min. Amine 119 (100mg, 0.2525 mmol) was then added at 0° C. The reaction mixture was thenbrought to room temperature and stirred overnight. After completion ofthe reaction, the reaction mixture was diluted with water and extractedwith ethyl acetate (3×15 ml). The organic layer was washed with water(3×10 ml), dried over anhydrous sodium sulfate, filtered andconcentrated over the rotary evaporator to get the crude product. Crudeproduct was purified by either by silica column chromatography orpreparative HPLC to obtain the pure products in 52-68% yields.

N-(2-Methyl-4-(4-picolinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120a)

¹H NMR (400 MHz, CD₃OD) δ: 2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m,3H), 7.6-7.8 (m, 4H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.6 (m, 2H), 9.1 (m,1H); HPLC Purity: 97.9%; LCMS, m/z found 516.1 (M+1)⁺.

N-(2-Methyl-4-(4-nicotinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120b)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 3H),7.6-7.8 (m, 4H), 8.2 (m, 1H), 8.6 (m, 2H), 8.9 (m, 2H), 9.1 (m, 1H),10.5 (s, 1H); HPLC Purity: 99.3%; LCMS, m/z found 516.1 (M+1)⁺.

N-(2-Methyl-4-(4-(6-methylpicolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120c)

¹H NMR (400 MHz, CDCl₃) δ: 2.1 (s, 3H), 2.3 (s, 3H), 3.2-3.8 (m, 8H),7.0-7.2 (m, 3H), 7.6-7.8 (m, 4H), 8.2 (m, 1H), 8.6 (m, 1H), 8.9 (m, 2H),9.1 (m, 1H), 10.5 (s, 1H); HPLC Purity: 95.5.0%; LCMS, m/z found 530.2(M+1)⁺.

N-(2-Methyl-4-(4-(3-(trifluoromethyl)picolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120d)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 2H),7.4-7.6 (m, 4H), 8.2 (m, 2H), 8.4 (m, 2H), 8.6-8.8 (m, 2H), 9.1 (m, 1H);HPLC Purity: 97.2.0%; LCMS, m/z found 584.1 (M+1)⁺.N-(4-(4-(3-Fluoropicolinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120e):

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 2H),7.4-7.6 (m, 5H), 8.2 (m, 1H), 8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity:99.6.0%; LCMS, m/z found 534.1 (M+1)⁺.

N-(4-(4-(4-Chloropicolinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120f)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 2H),7.4 (m, 1H), 7.5-7.8 (m, 4H), 8.0 (m, 1H), 8.2 (m, 2H), 8.6 (m, 1H), 9.1(m, 1H); HPLC Purity: 93.4%; LCMS, m/z found 550.1 (M+1)⁺.

N-(4-(4-(4-Fluoropicolinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120g)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 2H), 7.4(m, 1H), 7.5-7.8 (m, 4H), 8.0 (m, 1H), 8.2-8.4 (m, 3H), 9.1 (m, 1H);HPLC Purity: 99.2%; LCMS, m/z found 534.1 (M+1)⁺.

N-(2-Methyl-4-(4-(4-(trifluoromethyl)nicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120h)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 2H), 7.4(m, 1H), 7.5-7.6 (m, 3H), 8.4 (m, 3H), 8.7 (s, 1H), 8.8 (m, 1H), 9.1 (m,1H); HPLC Purity: 95.0%; LCMS, m/z found 584.1 (M+1)⁺.

N-(4-(4-(5-Chloronicotinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120i)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 3H), 7.4(m, 1H), 7.6-7.8 (m, 2H), 8.1 (m, 1H), 8.2 (m, 2H), 8.8 (m, 2H), 9.1 (m,1H); HPLC Purity: 98.1%; LCMS, m/z found 550.1 (M+1)⁺.

N-(4-(4-(5-Fluoronicotinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120j)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 2H),7.2-7.4 (m, 2H), 7.6-7.8 (m, 2H), 8.0-8.6 (m, 5H), 9.1 (m, 1H); HPLCPurity: 99.1%; LCMS, m/z found 534.3 (M+1)⁺.

N-(4-(4-(3-Fluoroisonicotinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120k)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 2H),7.2-7.4 (m, 2H), 7.6-7.8 (m, 2H), 8.0 (m, 1H), 8.2-8.6 (m, 4H), 9.1 (m,1H); HPLC Purity: 95.3%; LCMS, m/z found 534.1 (M+1)⁺.

N-(4-(4-(3-Chloroisonicotinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120l)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 1H),7.2-7.4 (m, 4H), 7.6-7.8 (m, 2H), 8.0 (m, 1H), 8.2-8.6 (m, 3H), 9.1 (m,1H); HPLC Purity: 99.8%; LCMS, m/z found 550.3 (M+1)⁺.

N-(4-(4-(2-Methoxynicotinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120m)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.2-7.4 (m, 4H),7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.2-8.6 (m, 3H), 9.1 (m, 1H); HPLC Purity:99.3%; LCMS, m/z found 546.3 (M+1)⁺.

N-(4-(4-(2-Methoxyisonicotinoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120n)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 6.7-7.0 (m, 4H),7.2 (m, 1H), 7.6 (m, 2H), 8.0 (m, 1H), 8.2-8.6 (m, 3H), 9.1 (m, 1H);HPLC Purity: 98.8%; LCMS, m/z found 546.3 (M+1)⁺.

N-(2-Methyl-4-(4-(5-(trifluoromethyl)picolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120o)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 2H), 7.2(m, 1H), 7.6 (m, 2H), 7.8 (m, 1H), 8.0 (m, 2H), 8.3-8.5 (m, 2H), 8.8 (s,1H), 9.1 (m, 1H); HPLC Purity: 91.8%; LCMS, m/z found 584.4 (M+1)⁺.

N-(2-Methyl-4-(4-(2-(trifluoromethyl)nicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120p)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 3H), 7.4(m, 1H), 7.6 (m, 4H), 8.0 (m, 1H), 8.3-8.5 (m, 1H), 8.8 (s, 1H), 9.1 (m,1H); HPLC Purity: 99.2%; LCMS, m/z found 584.3 (M+1)⁺.

N-(4-(4-Isonicotinoylpiperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120q)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 3H), 7.4(m, 2H), 7.6 (m, 2H), 8.3 (m, 2H), 8.5 (m, 2H), 9.1 (m, 1H); HPLCPurity: 94.5%; LCMS, m/z found 516.34 (M+1)⁺.

N-(2-Methyl-4-(4-(pyrazine-2-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120r)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 2H),7.4 (m, 1H), 7.6 (m, 2H), 8.0 (m, 1H), 8.3 (m, 2H), 8.6 (m, 1H), 8.8 (m,1H), 9.0 (s, 1H), 9.1 (m, 1H); HPLC Purity: 99.4%; LCMS, m/z found517.15 (M+1)⁺.

N-(4-(4-(2,3-Difluorobenzoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120s)

¹H NMR (400 MHz, CD₃OD) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 1H), 7.2(m, 4H), 7.4 (m, 1H), 8.7 (m, 2H), 8.2-8.5 (m, 3H), 9.1 (m, 1H); HPLCPurity: 98.6%; LCMS, m/z found 551.35 (M+1)⁺.

N-(4-(4-(2,6-Difluorobenzoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120t)

¹H NMR (400 MHz, CD₃OD) δ: 2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m,5H), 7.5 (m, 2H), 7.7 (m, 2H), 8.2-8.5 (m, 3H), 9.1 (m, 1H); HPLCPurity: 96.4%; LCMS, m/z found 551.35 (M+1)⁺.

N-(4-(4-(3,4-Difluorobenzoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120u)

¹H NMR (400 MHz, CD₃OD) δ: 2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0 (m, 2H),7.2-7.5 (m, 5H), 7.7 (m, 2H), 8.2-8.5 (m, 3H), 9.1 (m, 1H); HPLC Purity:97.9%; LCMS, m/z found 551.35 (M+1)⁺.

N-(4-(4-(2-Fluorobenzoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120v)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 4H),7.2-7.5 (m, 3H), 7.7 (m, 2H), 8.0-8.5 (m, 3H), 9.1 (m, 1H); HPLC Purity:93.6%; LCMS, m/z found 533.27 (M+1)⁺.

N-(2-Methyl-4-(4-(2-phenylacetyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120w)

¹H NMR (400 MHz, CDCl₃) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 3.9 (m, 2H), 7.0(m, 1H), 7.2-7.5 (m, 7H), 7.7 (m, 2H), 8.2-8.5 (m, 4H), 9.1 (m, 1H);HPLC Purity: 94.6%; LCMS, m/z found 529.35 (M+1)⁺.

N-(4-(4-(2-(4-Fluorophenyl)acetyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120x)

¹H NMR (400 MHz, CD₃OD) δ: 2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.5 (m,7H), 7.7 (m, 2H), 8.2-8.5 (m, 3H), 9.1 (m, 1H); HPLC Purity: 95.1%;LCMS, m/z found 547.0 (M+1)⁺.

N-(4-(4-(2-(4-Fluorophenyl)-2-methylpropanoyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120y)

¹H NMR (400 MHz, CDCl₃) δ:1.6 (s, 6H), 2.1 (s, 3H), 3.2-3.8 (m, 8H),6.9-7.0 (m, 3H), 7.2-7.5 (m, 3H), 7.7 (m, 2H), 8.2-8.5 (m, 4H), 9.1 (m,1H); HPLC Purity: 99.1%; LCMS, m/z found 575.1 (M+1)⁺.

N-(2-Methyl-4-(4-(thiazole-4-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120z)

¹H NMR (400 MHz, CD₃OD) δ: 2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m,3H), 7.6-7.8 (m, 2H), 8.1-8.5 (m, 4H), 9.1 (m, 2H); HPLC Purity: 98.6%;LCMS, m/z found 522.05 (M+1)⁺.

N-(4-(4-(1,2,3-Thiadiazole-4-carbonyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(120aa)

¹H NMR (400 MHz, DMSO-d₆) δ:2.1 (s, 3H), 3.2-3.8 (m, 8H), 7.0-7.2 (m,3H), 7.4-7.6 (m, 2H), 7.7 (m, 2H), 8.2-8.5 (m, 3H), 9.1 (m, 1H), 9.4 (s,1H), 9.6 (s, 1H); HPLC Purity: 99.1%; LCMS, m/z found 523.15 (M+1)⁺.

Cyclopentyl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ab)

¹H NMR (400 MHz, CDCl₃) δ:1.4-1.9 (m, 8H), 2.1 (s, 3H), 3.2-3.8 (m, 8H),5.1 (s, 1H), 7.0-7.2 (m, 1H), 7.4 (m, 3H), 7.7 (m, 1H), 8.2 (m, 1H),8.2-8.4 (m, 2H), 9.1 (m, 1H); HPLC Purity: 97.4%; LCMS, m/z found 523.30(M+1)⁺.

Cyclohexyl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ac)

¹H NMR (400 MHz, CDCl₃) δ:0.9 (m, 1H), 1.2-1.7 (m, 10H), 2.1 (s, 3H),3.2-3.8 (m, 8H), 5.1 (s, 1H), 7.0-7.4 (m, 3H), 7.6 (m, 2H), 8.1 (m, 1H),8.2-8.4 (m, 2H), 9.1 (m, 1H); HPLC Purity: 99.0%; LCMS, m/z found 537.19(M+1)³⁰.

Azetidin-3-yl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ad)

¹H NMR (400 MHz, DMSO-d₆) δ: 0.9 (m, 1H), 1.2-1.7 (m, 4H), 2.1 (s, 3H),3.2-3.8 (m, 8H), 5.1 (s, 1H), 7.0-7.4 (m, 3H), 7.6 (m, 2H), 8.3 (m, 2H),8.6 (m, 1H), 9.1 (m, 1H); HPLC Purity: 92.9%; LCMS, m/z found 510.31(M+1)⁺.

1-Methylazetidin-3-yl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ae)

¹H NMR (400 MHz, DMSO-d₆) δ:2.0 (s, 3H), 2.1 (s, 3H), 2.9 (m, 4H),3.2-3.8 (m, 8H), 5.1 (s, 1H), 7.0-7.4 (m, 3H), 7.8 (m, 2H), 8.3 (m, 2H),8.6 (m, 1H), 9.1 (m, 1H), 9.4 (s, 1H); HPLC Purity: 92.0%; LCMS, m/zfound 524.05 (M+1)⁺.

(Tetrahydrofuran-2-yl)methyl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120af)

¹H NMR (400 MHz, CDCl₃) δ: 1.1 (m, 2H), 1.8-2.0 (m, 4H), 2.1 (s, 3H),2.9 (m, 4H), 3.2-3.8 (m, 8H), 5.1 (s, 1H), 7.0-7.2 (m, 2H), 7.2-7.4 (m,1H), 7.6 (m, 2H), 8.0-8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity: 99.40%;LCMS, m/z found 539.15 (M+1)⁺.

2-Cyclopentylethyl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ag)

¹H NMR (400 MHz, CDCl₃) δ:1.2 (m, 4H), 1.4-1.6 (m, 8H), 2.0 (m, 1H), 2.1(s, 3H), 3.2-3.8 (m, 8H), 5.1 (s, 1H), 7.0-7.2 (m, 2H), 7.2-7.4 (m, 1H),7.6 (m, 2H), 8.0-8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity: 99.50%; LCMS,m/z found 551.1 (M+1)⁺.

Tetrahydrofuran-3-yl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ah)

¹H NMR (400 MHz, CDCl₃) δ:2.0 (m, 2H), 2.2 (s, 3H), 2.5 (s, 1H), 3.2-3.8(m, 8H), 4.0 (m, 4H), 5.1 (s, 1H), 7.0-7.2 (m, 1H), 7.2-7.4 (m, 2H), 7.6(m, 2H), 8.0-8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity: 99.50%; LCMS, m/zfound 525.05 (M+1)⁺.

2-Cyclohexylethyl4-(3-methyl-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ai)

¹H NMR (400 MHz, CDCl₃) δ:2.0 (m, 2H), 2.2 (s, 3H), 2.5 (s, 1H), 3.2-3.8(m, 8H), 4.0 (m, 4H), 5.1 (s, 1H), 7.0-7.2 (m, 1H), 7.2-7.4 (m, 2H), 7.6(m, 2H), 8.0-8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity: 99.50%; LCMS, m/zfound 525.05 (M+1)⁺.

N-(2-Fluoro-4-(4-picolinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120aj)

¹H NMR (400 MHz, CDCl₃) δ: 1.1 (m, 7H), 1.6-1.8 (m, 5H), 2.1 (s, 3H),3.2-3.8 (m, 8H), 4.7 (m, 1H), 7.0-7.2 (m, 2H), 7.4-7.6 (m, 3H), 8.0-8.4(m, 3H), 9.1 (m, 1H); HPLC Purity: 99.60%; LCMS, m/z found 565.45(M+1)⁺.

N-(2-Fluoro-4-(4-nicotinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120ak)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 2H), 7.4-7.6(m, 3H), 8.0-8.4 (m, 3H), 8.7 (m, 3H), 8.9 (m, 1H), 9.1 (m, 1H); HPLCPurity: 94.6%; LCMS, m/z found 520.25 (M+1)⁺.

N-(2-Fluoro-4-(4-isonicotinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120al)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 2H), 7.4-7.6(m, 3H), 8.0-8.4 (m, 3H), 8.7 (m, 3H), 8.9 (m, 1H), 9.1 (m, 1H), 10.5 (s1H); HPLC Purity: 93.8%; LCMS, m/z found 518.46 (M+1)⁺.

N-(2-Fluoro-4-(4-(pyrazine-2-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120am)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.4 (m, 3H), 7.6-7.8(m, 2H), 8.0-8.4 (m, 2H), 8.7 (m, 3H), 9.1 (m, 1H), 10.0 (s 1H); HPLCPurity: 99.8%; LCMS, m/z found 521.24 (M+1)⁺.

N-(4-(4-(2,6-Difluorobenzoyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(120an)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.4 (m, 3H), 7.6-7.8(m, 5H), 8.0-8.4 (m, 3H), 9.1 (m, 1H), 10.0 (s, 1H); HPLC Purity: 99.8%;LCMS, m/z found 555.21 (M+1)⁺.

N-(4-(4-(3,4-Difluorobenzoyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(120ao)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.4 (m, 4H), 7.6-7.8(m, 4H), 8.0-8.4 (m, 2H), 8.7 (m, 1H), 9.1 (m, 1H), 10.0 (s 1H); HPLCPurity: 97.9%; LCMS, m/z found 555.14 (M+1)⁺.

N-(2-Fluoro-4-(4-(2-fluorobenzoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120ap):108

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 3H), 7.2-7.4 (m,4H), 7.6-7.8 (m, 2H), 8.0-8.4 (m, 2H), 8.9 (s, 1H), 9.1 (m, 1H); HPLCPurity: 97.8%; LCMS, m/z found 537.21 (M+1)⁺.

N-(2-Fluoro-4-(4-(2-phenylacetyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120aq)

¹H NMR (400 MHz, CDCl₃) δ:2.4 (s, 2H), 7.0-7.2 (m, 3H), 7.2-7.4 (m, 4H),7.6-7.8 (m, 4H), 8.0-8.4 (m, 2H), 9.1 (m, 1H); HPLC Purity: 98.4%; LCMS,m/z found 533.26 (M+1)⁺.

N-(2-Fluoro-4-(4-(2-(4-fluorophenyl)acetyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120ar)

¹H NMR (400 MHz, CD₃OD) δ: 3.2-3.8 (m, 8H), 3.9 (s, 2H), 7.0-7.2 (m,4H), 7.2-7.4 (m, 2H), 7.6-7.8 (m, 3H), 8.2 (m, 1H), 8.4 (m, 2H), 9.1 (m,1H); HPLC Purity: 93.1%; LCMS, m/z found 551.23 (M+1)⁺.

N-(2-Fluoro-4-(4-(2-(4-fluorophenyl)-2-methylpropanoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120as)

¹H NMR (400 MHz, CDCl₃) δ:1.3 (s, 6H), 3.2-3.8 (m, 8H), 7.0-7.2 (m, 3H),7.2-7.4 (m, 2H), 7.6-7.8 (m, 3H), 8.2 (m, 1H), 8.4 (m, 2H), 8.9 (s, 1H),9.1 (m, 1H); HPLC Purity: 98.3%; LCMS, m/z found 579.22 (M+1)⁺.

N-(2-Fluoro-4-(4-(Thiazole-4-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120at)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 3H), 7.2-7.4(m, 2H), 7.6-7.8 (m, 3H), 8.2 (m, 1H), 8.9 (m, 2H), 9.0 (s, 1H), 9.5 (d,1H); HPLC Purity: 91.6%; LCMS, m/z found 526.19 (M+1)⁺.

N-(4-(4-(1,2,3-Thiadiazole-4-carbonyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(120au)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 3H), 7.6-7.8(m, 2H), 8.2-8.4 (m, 3H), 9.0 (m, 1H), 9.5 (s, 1H); HPLC Purity: 91.6%;LCMS, m/z found 526.19 (M+1)⁺.

Cyclohexyl4-(3-fluoro-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120av)

¹H NMR (400 MHz, DMSO-d₆) δ:1.2-1.8 (m, 10H), 3.2-3.8 (m, 8H), 4.8 (m,1H), 7.0-7.2 (m, 2H), 7.6-7.8 (m, 3H), 8.2 (m, 1H), 8.2-8.4 (m, 2H), 8.9(m, 1H), 9.0 (s, 1H), 9.5 (d, 1H); HPLC Purity: 91.6%; LCMS, m/z found526.19 (M+1)⁺.

N-(2-Chloro-4-(4-picolinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120aw)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 7.0-7.2 (m, 2H), 7.6-7.8(m, 3H), 8.2 (m, 3H), 8.2-8.4 (m, 2H), 8.9 (m, 1H), 9.0 (s, 1H), 10.5(s, 1H); HPLC Purity: 99.1%; LCMS, m/z found 537.1 (M+1)⁺.

N-(2-Hydroxy-4-(4-picolinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120ax)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 4.8 (s, 1H), 7.0-7.2 (m,2H), 7.6-7.8 (m, 3H), 8.2 (m, 3H), 8.2-8.4 (m, 2H), 8.9 (m, 1H), 9.0 (s,1H), 10.5 (s, 1H); HPLC Purity: 98.1%; LCMS, m/z found 518.2 (M+1)⁺.

N-(4-(4-Isonicotinoylpiperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120ay)

¹H NMR (400 MHz, DMSO-d₆) δ: 3.2-3.8 (m, 8H), 6.4 (m, 1H), 7.0-7.2 (m,2H), 7.6-7.8 (m, 2H), 8.0 (m, 1H), 8.2-8.4 (m, 3H), 8.8 (s, 1H), 8.9 (s,1H), 9.0 (s, 1H); HPLC Purity: 95.0%; LCMS, m/z found 532.2 (M+1)⁺.

N-(3-Methoxy-4-(4-(6-methylpicolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120az)

¹H NMR (400 MHz, CD₃OD) δ: 2.2 (s, 3H), 3.2-3.8 (m, 8H), 3.9 (s, 3H),6.7 (m, 3H), 7.2 (m, 2H), 7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H),9.0 (s, 1H); HPLC Purity: 98.8%; LCMS, m/z found 546.2 (M+1)⁺.

N-(4-(4-(3-Fluoropicolinoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120ba)

¹H NMR (400 MHz, DMSO-d₆)) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.7-7.0 (m,3H), 7.2 (m, 2H), 7.6-7.8 (m, 3H), 8.1 (s, 1H), 8.4 (m, 2H), 9.0 (s,1H); HPLC Purity: 98.8%; LCMS, m/z found 550.2 (M+1)⁺.

N-(4-(4-(5-Fluoropicolinoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bb)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.7-7.0 (m,3H), 7.2 (m, 2H), 7.6-7.8 (m, 3H), 8.1 (s, 1H), 8.4 (m, 1H), 9.0 (s,1H), 9.3 (s, 1H), 10.5 (s, 1H); HPLC Purity: 98.9%; LCMS, m/z found550.2 (M+1)⁺.

N-(3-Methoxy-4-(4-(5-(trifluoromethyl)picolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bc)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.6-6.9 (m,3H), 7.2 (m, 2H), 7.6-7.8 (m, 3H), 8.2-8.4 (m, 2H), 8.9 (m, 1H), 9.0 (s,1H); HPLC Purity: 99.2%; LCMS, m/z found 600.3 (M+1)⁺.

N-(4-(4-(5-Fluoronicotinoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bd)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6 (m, 3H), 8.0 (m, 1H), 8.2-8.6 (m, 4H), 9.1 (m, 1H);HPLC Purity: 99.5%; LCMS, m/z found 550.3 (M+1)⁺.

N-(4-(4-(3-Chloroisonicotinoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120be)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.6-8.8 (m, 2H),9.1 (m, 1H); HPLC Purity: 98.2%; LCMS, m/z found 566.25 (M+1)⁺.

N-(4-(4-(3-Fluoroisonicotinoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bf)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.6-8.8 (m, 2H),9.1 (m, 1H); HPLC Purity: 98.9%; LCMS, m/z found 550.35 (M+1)⁺.

N-(4-(4-(5-Chloronicotinoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bg)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.3 (m, 2H), 7.6 (m, 2H), 8.0 (m, 1H), 8.2-8.4 (m, 2H),8.6-8.8 (m, 2H), 9.1 (m, 1H); HPLC Purity: 98.5%; LCMS, m/z found 566.3(M+1)⁺.

N-(3-Methoxy-4-(4-(4-(trifluoromethyl)nicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bh)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6 (m, 2H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.4-8.6 (m, 2H),8.9 (m, 1H), 9.1 (m, 1H); HPLC Purity: 90.6%; LCMS, m/z found 600.35(M+1)⁺.

N-(3-Methoxy-4-(4-nicotinoylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bi)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.2-7.6 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.6-8.6 (m,2H), 8.9 (m, 1H), 9.1 (m, 1H); HPLC Purity:96.5%; LCMS, m/z found 532.35(M+1)⁺.

N-(4-(4-(5-Chloropicolinoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bj)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6-7.8 (m, 4H), 8.0 (m, 1H), 8.2-8.4 (m, 3H), 9.1 (m, 1H);HPLC Purity: 92.08%; LCMS, m/z found 566.3 (M+1)⁺.

N-(3-Methoxy-4-(4-(3-(trifluoromethyl)picolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bk)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.8 (m, 1H),9.1 (m, 1H); HPLC Purity: 92.08%; LCMS, m/z found 566.3 (M+1)⁺.

N-(3-Methoxy-4-(4-(2-(trifluoromethyl)nicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bl)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6-7.8 (m, 4H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.8 (m, 1H),9.1 (m, 1H); HPLC Purity: 96.5%; LCMS, m/z found 600.3 (M+1)⁺.

N-(3-Methoxy-4-(4-(3-methoxyisonicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bm)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 3H), 7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.8 (m, 1H),9.1 (m, 1H); HPLC Purity: 93.2%; LCMS, m/z found 562.3 (M+1)⁺.

N-(3-Methoxy-4-(4-(2-methoxyisonicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bn)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 3H), 7.6-7.8 (m, 2H), 8.0 (m, 1H), 8.2-8.4 (m, 3H), 8.8 (m, 1H),9.1 (m, 1H); HPLC Purity: 98.5%; LCMS, m/z found 562.4 (M+1)⁺.

N-(3-Methoxy-4-(4-(pyrazine-2-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bo)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.6-7.8 (m, 2H), 8.0 (m, 1H), 8.2-8.4 (m, 4H), 9.1 (s, 1H),9.2 (s, 1H); HPLC Purity: 98.9%; LCMS, m/z found 533.1 (M+1)⁺.

N-(4-(4-(2-Fluoro-3-methoxybenzoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120 bp)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 4.0 (s, 3H),6.4 (m, 1H), 7.0 (m, 3H), 7.2 (m, 2H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m,2H), 9.1 (s, 1H); HPLC Purity: 99.3%; LCMS, m/z found 579.2 (M+1)⁺.

N-(4-(4-(2-Fluorobenzoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bq)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.2-7.4 (m, 6H), 8.8 (m, 1H), 8.0 (m, 3H), 8.6 (s, 1H), 9.1 (s, 1H);HPLC Purity: 99.5%; LCMS, m/z found 549.2 (M+1)⁺.

N-(4-(4-(2,3-Difluorobenzoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120br)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0-7.4 (m, 5H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 2H), 8.6 (s, 1H), 9.1(s, 1H); HPLC Purity: 96.1%; LCMS, m/z found 567.1 (M+1)⁺.

N-(4-(4-(3,4-Difluorobenzoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bs)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0-7.4 (m, 5H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 2H), 8.6 (s, 1H), 9.1(s, 1H); HPLC Purity: 98.9%; LCMS, m/z found 567.1 (M+1)⁺.

N-(4-(4-(2,6-Difluorobenzoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bt)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0-7.4 (m, 4H), 7.6 (m, 3H), 8.0 (m, 1H), 8.4 (m, 2H), 9.1 (s, 1H);HPLC Purity: 98.4%; LCMS, m/z found 567.0 (M+1)⁺.

N-(3-Methoxy-4-(4-(2-phenylacetyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bu)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 2H), 7.2-7.4 (m, 5H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 2H), 9.1(s, 1H); HPLC Purity: 99.7%; LCMS, m/z found 545.2 (M+1)⁺.

N-(3-Methoxy-4-(4-(2-(4-(trifluoromethyl)phenyl)acetyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bv)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),7.0 (m, 3H), 7.2-7.4 (m, 2H), 7.6 (m, 3H), 8.0 (m, 1H), 8.4 (m, 2H), 8.6(s, 1H), 9.1 (s, 1H); HPLC Purity: 99.1%; LCMS, m/z found 613.1 (M+1)⁺.

N-(3-Methoxy-4-(4-(2-methyl-2-phenylpropanoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bw)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),6.9-7.0 (m, 2H), 7.2-7.4 (m, 4H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 2H),8.6 (s, 1H), 9.1 (s, 1H); HPLC Purity: 95.3%; LCMS, m/z found 573.45(M+1)⁺.

N-(4-(4-(2-(4-Fluorophenyl)-2-methylpropanoyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120bx)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),6.9-7.2 (m, 5H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 2H), 8.6 (s, 1H), 9.1(s, 1H); HPLC Purity: 99.1%; LCMS, m/z found 591.3 (M+1)⁺.

N-(4-(4-(1,2,3-Thiadiazole-4-carbonyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(120by)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),6.9-7.2 (m, 2H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 2H), 8.6 (s, 1H), 9.1(m, 1H); HPLC Purity: 99.0%; LCMS, m/z found 539.3 (M+1)⁺.

N-(3-Methoxy-4-(4-(thiazole-4-carbonyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120bz)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.4 (m, 1H),6.9-7.2 (m, 2H), 7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 1H), 8.6 (s, 1H), 8.8(s, 1H), 9.1 (m, 1H); HPLC Purity: 99.6%; LCMS, m/z found 538.3 (M+1)⁺.

2-Cyclopentylethyl4-(2-methoxy-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ca)

¹H NMR (400 MHz, CDCl₃) δ: 1.2 (m, 4H), 1.6 (m, 8H), 3.2-3.8 (m, 8H),3.9 (s, 3H), 4.7 (m, 1H), 6.4 (m, 1H), 6.9-7.2 (m, 2H), 7.6 (m, 2H), 8.0(m, 1H), 8.4 (m, 1H), 8.6 (s, 1H), 8.8 (s, 1H), 9.1 (m, 1H); HPLCPurity: 99.8%; LCMS, m/z found 567.1 (M+1)⁺.

Tetrahydrofuran-3-yl4-(2-methoxy-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120cb)

¹H NMR (400 MHz, CDCl₃) δ:2.0 (m, 2H), 2.2 (m, 1H), 3.0-3.6 (m, 4H),3.2-3.8 (m, 8H), 3.9 (s, 3H), 5.2 (s, 1H), 6.4 (m, 1H), 6.9-7.2 (m, 2H),7.6 (m, 2H), 8.0 (m, 1H), 8.4 (m, 1H), 8.6 (s, 1H), 8.8 (s, 1H), 9.1 (m,1H); HPLC Purity: 96.2%; LCMS, m/z found 541.05 (M+1)⁺.

2-Cyclohexylethyl4-(2-methoxy-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120cc)

¹H NMR (400 MHz, CDCl₃) δ:1.2 (m, 10H), 1.6-1.8 (m, 4H), 3.2-3.8 (m,8H), 3.9 (s, 3H), 4.7 (s, 1H), 6.4 (m, 1H), 6.9-7.0 (m, 2H), 7.6 (m,2H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.6 (s, 1H), 9.1 (m, 1H); HPLCPurity: 97.7%; LCMS, m/z found 581.4 (M+1)⁺.

N-(2-Methoxy-4-(4-(6-methylpicolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120cd)

¹H NMR (400 MHz, CDCl₃) δ: 2.1 (s, 3H), 3.2-3.8 (m, 8H), 3.9 (s, 3H),6.7 (s, 1H), 6.9 (m, 1H), 7.2 (m, 1H), 7.4-7.8 (m, 5H), 8.0 (m, 1H),8.2-8.4 (m, 2H), 8.8 (s, 1H), 9.1 (m, 1H); HPLC Purity: 99.6%; LCMS, m/zfound 546.3 (M+1)⁺.

N-(2-Methoxy-4-(4-(3-(trifluoromethyl)picolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120ce)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.7 (s, 1H),6.9 (m, 1H), 7.4-7.7 (m, 4H), 8.0 (m, 2H), 8.2-8.4 (m, 2H), 8.8 (s, 1H),9.1 (m, 1H); HPLC Purity: 99.9%; LCMS, m/z found 600.3 (M+1)⁺.

N-(4-(4-(3-Fluoropicolinoyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(120cf)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.4-7.7 (m, 5H), 8.0 (m, 2H), 8.2-8.4 (m, 2H), 8.8 (s, 1H), 9.1 (m, 1H);HPLC Purity: 99.8%; LCMS, m/z found 550.3 (M+1)⁺.

N-(2-Methoxy-4-(4-(5-(trifluoromethyl)picolinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120cg)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 4H), 8.0 (m, 2H), 8.2-8.4 (m, 2H), 8.8 (s, 1H), 8.9 (m, 1H),9.1 (m, 1H); HPLC Purity: 99.6%; LCMS, m/z found 600.3 (M+1)⁺.

N-(4-(4-(5-Chloropicolinoyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(120ch)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 5H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.8 (s, 1H), 8.9 (m, 1H),9.1 (m, 1H); HPLC Purity: 99.3%; LCMS, m/z found 566.3 (M+1)⁺.

N-(4-(4-(5-Fluoropicolinoyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(120ci)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 5H), 8.0 (m, 1H), 8.2-8.4 (m, 3H), 8.8 (s, 1H), 9.1 (m, 1H);HPLC Purity: 99.4%; LCMS, m/z found 550.3 (M+1)⁺.

N-(2-Methoxy-4-(4-(4-(trifluoromethyl)nicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120cj)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 4H), 8.2-8.4 (m, 2H), 8.6 (s, 1H), 8.8 (m, 2H), 9.1 (m, 1H);HPLC Purity: 99.9%; LCMS, m/z found 600.3 (M+1)⁺.

N-(4-(4-(5-Chloronicotinoyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(120ck)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 4H), 8.0 (m, 1H), 8.4-8.6 (m, 2H), 8.7 (s, 1H), 8.8 (s, 1H),9.1 (m, 1H); HPLC Purity: 95.7%; LCMS, m/z found 566.3 (M+1)⁺.

N-(4-(4-(5-Fluoronicotinoyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(120cl)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 4H), 8.0 (m, 1H), 8.4-8.6 (m, 2H), 8.7 (s, 1H), 8.8 (s, 1H),9.1 (m, 1H); HPLC Purity: 89.4%; LCMS, m/z found 550.3 (M+1)⁺.

N-(4-(4-(3-Chloroisonicotinoyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(120 cm)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.4-8.6 (m, 4H), 8.9 (s, 1H), 9.1 (m, 1H);HPLC Purity: 98.5%; LCMS, m/z found 566.3 (M+1)⁺.

N-(4-(4-(3-Fluoroisonicotinoyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(120cn)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9 (m, 2H),7.6-7.8 (m, 4H), 8.0 (m, 1H), 8.4-8.6 (m, 3H), 8.9 (s, 1H), 9.1 (m, 1H);HPLC Purity: 94.9%; LCMS, m/z found 550.3 (M+1)⁺.

N-(2-Methoxy-4-(4-(2-methoxyisonicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120co)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.8 (s, 3H), 3.9 (s, 3H),6.6-6.9 (m, 4H), 7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 3H), 8.9 (s,1H), 9.1 (m, 1H); HPLC Purity: 97.3%; LCMS, m/z found 562.3 (M+1)⁺.

N-(2-Methoxy-4-(4-(2-(trifluoromethyl)nicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120cp)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.6 (s, 1H),6.9 (m, 1H), 7.6-7.8 (m, 5H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 8.9 (s, 1H),9.1 (m, 1H); HPLC Purity: 99.7%; LCMS, m/z found 600.3 (M+1)⁺.

N-(2-Methoxy-4-(4-(2-methoxynicotinoyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(120cq)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.8 (s, 3H), 3.9 (s, 3H),6.6 (s, 1H), 6.9 (m, 1H), 7.6-7.8 (m, 4H), 8.0 (m, 1H), 8.2-8.4 (m, 3H),8.9 (s, 1H), 9.1 (m, 1H); HPLC Purity: 99.8%; LCMS, m/z found 562.4(M+1)⁺.

Tetrahydrofuran-3-yl4-(3-methoxy-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120cr):

¹H NMR (400 MHz, CDCl₃) δ:2.2 (m, 2H), 3.2-3.8 (m, 8H), 3.9 (s, 3H), 4.0(m, 2H), 5.0 (m, 1H), 6.9 (m, 2H), 7.6-7.8 (m, 3H), 8.0 (m, 1H), 8.2-8.4(m, 2H), 9.1 (m, 1H); HPLC Purity: 98.1%; LCMS, m/z found 541.0 (M+1)⁺.

(Tetrahydrofuran-2-yl)methyl4-(3-methoxy-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120cs)

¹H NMR (400 MHz, CDCl₃) δ:1.2 (m, 2H), 1.2 (m, 2H), 1.6 (m, 1H), 2.0 (m,2H), 3.2-3.8 (m, 8H), 3.9 (s, 3H), 4.0 (m, 2H), 6.9-7.0 (m, 2H), 7.6-7.8(m, 3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 9.1 (m, 1H); HPLC Purity: 99.0%;LCMS, m/z found 555.1 (M+1)⁺.

2-Cyclopentylethyl4-(3-methoxy-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120ct)

¹H NMR (400 MHz, CDCl₃) δ:1.2 (m, 6H), 1.6 (m, 12H), 2.0 (m, 2H),3.2-3.8 (m, 8H), 3.9 (s, 3H), 4.0 (m, 2H), 6.9-7.0 (m, 2H), 7.6-7.8 (m,3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 9.1 (m, 1H); HPLC Purity: 99.0%;LCMS, m/z found 589.1 (M+1)⁺.

2-Cyclohexylethyl4-(3-methoxy-4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate(120cu)

¹H NMR (400 MHz, CDCl₃) δ: 1.0 (m, 2H), 1.2 (m, 6H), 1.6 (m, 6H),3.2-3.8 (m, 8H), 3.9 (s, 3H), 4.6 (m, 1H), 6.9-7.0 (m, 2H), 7.6-7.8 (m,3H), 8.0 (m, 1H), 8.2-8.4 (m, 2H), 9.1 (m, 1H); HPLC Purity: 98.3%;LCMS, m/z found 581.4 (M+1)⁺.

Synthesis of Piperazine Derivatives with 3-trifluoromethyl or3-trifluoromethoxy Substituted Phenyl Rings

General procedure for the synthesis of sulfonamide 122: To a stirredsolution of amine 121 (30.3 mmol) in DMF (20 ml per gm) under nitrogenatmosphere was added sodium hydride (90.9 mmol) portion-wise at 0° C.and stirred for 10 min at RT. Quinoline-8-sulfonyl chloride 89 (8.94 gm,39.4 mmol) was then added to the reaction mixture at 0° C. The resultingmixture was stirred for further 30 min at RT. After completion of thereaction, most of the solvent was removed under low pressure. Theresidue was diluted with ice water-EtOAc mixture and the pH was broughtto 7.0 using saturated solution of NaH₂PO₄. The product was thenextracted in EtOAc, washed with water and brine, dried over sodiumsulphate and the solvent removed under low pressure. The resulting crudeproduct (80%) was then to the next step without further purification.

General procedure for the synthesis of hydrolysis product 123: To astirred solution of sulfonamide 122 (22.4 mmol) in THF:H₂O (1:1) undernitrogen atmosphere was added solid LiOH (9.4 gm, 224 mmol) at RT. Thesolution was then refluxed for 6 hr. After completion of the reaction,the reaction mixture was washed with ethyl acetate (2×100 ml) to removenon polar impurities. The aqueous layer was acidified (pH 4) with citricacid solution. The resultant precipitate was filtered out and air-dried.The traces of water were removed by co-distillation with toluene. Theresultant off white solid (80%) was taken to the next step withoutfurther purification.

General procedure for the synthesis of sulfonamide 124: EDCI (3.8 g,19.8 mmol) and HOBT (2.67 g, 19.8 mmol) were added to a stirred solutionof the acid 123 (19.8 mmol) in anhydrous DMF. The temperature of themixture was reduced to 0° C., at which time DIPEA (11 ml, 59.45 mmol)was added under nitrogen atmosphere and the resultant solution (orsuspension) was stirred at room temperature for 30 min. Boc-piperazine(3.68 g, 19.8 mmol) was then added at 0° C. The reaction mixture wasthen brought to room temperature and stirred overnight. After completionof the reaction, the reaction mixture was diluted with water andextracted with ethyl acetate (3×70 ml). The organic layer was washedwith water (3×50 ml), dried over anhydrous sodium sulfate, filtered andconcentrated over the rotary evaporator to get the crude product.

Crude product was purified by column chromatography (60-120 silica gel,2% MeOH-DCM) to get pure product, Boc-125 (8.0 g, 82%) as an off-whitesolid, which was subjected to the treatment with methanolic HCl (100 ml)for 2 hr at RT. After the complete cleavage of Boc-group, the solventwas removed under low pressure, to give the crude product as an HClsalt. The aqueous solution of the salt was washed with diethylether andbasified with NaHCO₃ (pH 10). The desired product was then partitionedinto ethyl acetate, dried with anhydrous Na₂SO₄ and the solvent removedunder low pressure to get the free amine 125 as off white solid (6.0 g,95%).

General procedure for the synthesis of amides 125a-g: EDCI (48 mg,0.2525 mmol) and HOBT (34 mg, 0.2525 mmol) were added to a stirredsolution of the Ar—COOH (0.2525 mmol) in anhydrous DMF. The temperatureof the mixture was reduced to 0° C., at which time DIPEA (139 μl, 0.7575mmol) was added under nitrogen atmosphere and the resultant solution (orsuspension) was stirred at room temperature for 30 min. Amine 124 (100mg, 0.2525 mmol) was then added at 0° C. The reaction mixture was thenbrought to room temperature and stirred overnight. After completion ofthe reaction, the reaction mixture was diluted with water and extractedwith ethyl acetate (3×15 ml). The organic layer was washed with water(3×10 ml), dried over anhydrous sodium sulfate, filtered andconcentrated over the rotary evaporator to get the crude product. Crudeproduct was purified by either by silica column chromatography orpreparative HPLC to obtain the pure products in 52-70% yields.

N-(4-(4-Isonicotinoylpiperazine-1-carbonyl)-2-(trifluoromethyl)phenyl)quinoline-8-sulfonamide(125a)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.2 (m, 2H), 7.4-7.7 (m,4H), 8.0 (m, 2H), 8.4-8.8 (m, 4H), 9.1 (m, 1H); HPLC Purity: 99.0%;LCMS, m/z found 570.1 (M+1)⁺.

N-(4-(4-Nicotinoylpiperazine-1-carbonyl)-2-(trifluoromethyl)phenyl)quinoline-8-sulfonamide(125b)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.2 (m, 2H), 7.4-7.9 (m,5H), 8.0-8.4 (m, 2H), 8.4-8.8 (m, 3H), 9.1 (m, 1H); HPLC Purity: 98.4%;LCMS, m/z found 570.1 (M+1)⁺.

N-(4-(4-(Pyrazine-2-carbonyl)piperazine-1-carbonyl)-2-(trifluoromethyl)phenyl)quinoline-8-sulfonamide(125c)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.4-7.9 (m, 5H), 8.0-8.4 (m,2H), 8.4-8.8 (m, 3H), 9.1 (m, 2H); HPLC Purity: 90.0%; LCMS, m/z found571.1 (M+1)⁺.

N-(4-(4-(2,6-Difluorobenzoyl)piperazine-1-carbonyl)-2-(trifluoromethyl)phenyl)quinoline-8-sulfonamide(125d)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.0 (m, 1H), 7.2-7.9 (m,6H), 8.2-8.8 (m, 3H), 9.1 (m, 2H); HPLC Purity: 90.0%; LCMS, m/z found571.1 (M+1)⁺.

N-(4-(4-(2-Fluoro-3-methoxybenzoyl)piperazine-1-carbonyl)-2-(trifluoromethyl)phenyl)quinoline-8-sulfonamide(125e)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 3.9 (s, 3H), 6.9-7.2 (m,2H), 7.4-7.9 (m, 5H), 8.0-8.6 (m, 3H), 9.1 (m, 2H); HPLC Purity: 99.0%;LCMS, m/z found 617.1 (M+1)⁺.

N-(4-(4-(1,2,3-Thiadiazole-4-carbonyl)piperazine-1-carbonyl)-2-(trifluoromethyl)phenyl)quinoline-8-sulfonamide(125f)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.4-7.9 (m, 4H), 8.1-8.6 (m,3H), 9.0 (m, 2H), 9.2 (s, 1H); HPLC Purity: 99.0%; LCMS, m/z found 557.1(M+1)⁺.

N-(4-(4-(Thiazole-4-carbonyl)piperazine-1-carbonyl)-2-(trifluoromethyl)phenyl)quinoline-8-sulfonamide(125g)

¹H NMR (400 MHz, CDCl₃) δ: 3.2-3.8 (m, 8H), 7.4-7.9 (m, 3H), 8.1-8.6 (m,4H), 8.8 (s, 1H), 9.0 (m, 1H); HPLC Purity: 99.3%; LCMS, m/z found 576.1(M+1)⁺.

Synthesis Homopiperazine Compounds

General procedure for the synthesis of sulfonamide 127: To a stirredsolution of amine 126 (30.3 mmol) under nitrogen atmosphere was addedpyridine (50 ml) at 0° C. and stirred for 10 min. Quinoline-8-sulfonylchloride 89 (8.94 gm, 39.4 mmol) was then added to the reaction mixtureat the same temperature. The resulting mixture was stirred for 16 hr atRT. After completion of the reaction, the solvent was removed under lowpressure. The traces of pyridine were removed by co-distillation withtoluene. Diethylether was added to the resulting residue, and the solidproduct was filtered out and air-dried. The resulting crude product (8.0gm, 74%) was taken to the next step without further purification.

General procedure for the synthesis of acid 128: To a stirred solutionof sulfonamide 127 (22.4 mmol) in THF:H₂O (1:1) under nitrogenatmosphere was added solid LiOH (9.4 gm, 224 mmol) at RT. The solutionwas then refluxed for 6 hr. After completion of the reaction, thereaction mixture was washed with ethyl acetate (2×100 ml) to remove nonpolar impurities. The aqueous layer was acidified (pH 4) with citricacid solution. The resultant precipitate was filtered out and air-dried.The traces of water were removed by co-distillation with toluene. Theresultant off white solid (80%) was taken to the next step withoutfurther purification.

General procedure for the synthesis of amine 129: EDCI (3.8 g, 19.8mmol) and HOBT (2.67 g, 19.8 mmol) were added to a stirred solution ofthe acid 128 (19.8 mmol) in anhydrous DMF.

The temperature of the mixture was reduced to 0° C., at which time DIPEA(11 ml, 59.45 mmol) was added under nitrogen atmosphere and theresultant solution (or suspension) was stirred at room temperature for30 min. Boc-homopiperazine (19.8 mmol) was then added at 0° C. Thereaction mixture was then brought to room temperature and stirredovernight. After completion of the reaction, the reaction mixture wasdiluted with water and extracted with ethyl acetate (3×70 ml). Theorganic layer was washed with water (3×50 ml), dried over anhydroussodium sulfate, filtered and concentrated over the rotary evaporator toget the crude product. Crude product was purified by columnchromatography (60-120 silica gel, 2% MeOH-DCM) to get pure product,Boc-129 (85%) as an off-white solid, which was subjected to thetreatment with methanolic HCl (100 ml) for 2 hr at RT. After thecomplete cleavage of Boc-group, the solvent was removed under lowpressure, to give the crude product as an HCl salt. The aqueous solutionof the salt was washed with diethylether and basified with NaHCO₃ (pH10). The desired product was then partitioned into ethyl acetate, driedwith anhydrous Na₂SO₄ and the solvent removed under low pressure to getthe free amine 129 as off white solid (92%).

General procedure for the synthesis of amides 130a-r: EDCI (48 mg,0.2525 mmol) and HOBT (34 mg, 0.2525 mmol) were added to a stirredsolution of the Ar—COOH (0.2525 mmol) in anhydrous DMF. The temperatureof the mixture was reduced to 0° C., at which time DIPEA (139 μl, 0.7575mmol) was added under nitrogen atmosphere and the resultant solution (orsuspension) was stirred at room temperature for 30 min. Amine 129(0.2525 mmol) was then added at 0° C. The reaction mixture was thenbrought to room temperature and stirred overnight.

After completion of the reaction, the reaction mixture was diluted withwater and extracted with ethyl acetate (3×15 ml). The organic layer waswashed with water (3×10 ml), dried over anhydrous sodium sulfate,filtered and concentrated over the rotary evaporator to get the crudeproduct. Crude product was purified by either by silica columnchromatography or preparative HPLC to obtain the pure products in 54-72%yields.

N-(4-(4-(2-(2-Fluorophenyl)acetyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130a)

¹H NMR (400 MHz, DMSOd₆) δ: 3.0-3.8 (m, 10H), 7.0-7.4 (m, 8H), 7.5-7.8(m, 2H), 8.0-8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity: 98.1%; LCMS, m/zfound 547.4 (M+1)⁺.

N-(4-(4-(2-(5-Fluoropyridin-2-yl)-2-methylpropanoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130b)

¹H NMR (400 MHz, DMSOd₆) δ:1.4 (s, 6H), 3.0-3.8 (m, 10H), 7.0-7.2 (m,6H), 7.6-7.8 (m, 2H), 8.0-8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity: 98.6%;LCMS, m/z found 575.4 (M+1)⁺.

N-(4-(4-(2-Fluoro-3-methoxybenzoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130c)

¹H NMR (400 MHz, DMSOd₆) δ: 3.0-3.8 (m, 10H), 3.9 (s, 3H), 6.9-7.2 (m,7H), 7.6-7.8 (m, 2H), 8.2-8.4 (m, 3H), 9.1 (m, 1H); HPLC Purity: 98.2%;LCMS, m/z found 561.5 (M+1)⁺.

N-(4-(4-Picolinoyl-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130d)

¹H NMR (400 MHz, DMSOd₆) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 5H), 9.1 (m, 1H); HPLC Purity: 99.4%; LCMS, m/z found516.0 (M+1)⁺.

N-(4-(4-(2,6-Difluorobenzoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130e)

¹H NMR (400 MHz, DMSOd₆) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 4H), 9.1 (m, 1H); HPLC Purity: 98.7%; LCMS, m/z found551.3 (M+1)⁺.

N-(4-(4-(2-(4-Fluorophenyl)acetyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130f)

¹H NMR (400 MHz, DMSOd₆) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 5H), 9.1 (m, 1H); HPLC Purity: 99.6%; LCMS, m/z found547.2 (M+1)⁺.

N-(4-(4-(4-Chlorobenzoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130g)

¹H NMR (400 MHz, DMSOd₆) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 5H), 9.1 (m, 1H); HPLC Purity: 99.4%; LCMS, m/z found549.3 (M+1)⁺.

N-(4-(4-(2-(4-(Trifluoromethyl)phenyl)acetyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130h)

¹H NMR (400 MHz, DMSOd₆) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 5H), 9.1 (m, 1H); HPLC Purity: 99.2%; LCMS, m/z found597.2 (M+1)⁺.

N-(4-(4-(2,4-Dichlorobenzoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide2,2,2-trifluoroacetate (130i)

¹H NMR (400 MHz, DMSOd₆) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 3H), 8.5 (s, 1H), 9.1 (m, 1H); HPLC Purity: 94.4%;LCMS, m/z found 582.47 (M+1)⁺.

N-(4-(4-(2,3-Difluorobenzoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130j)

¹H NMR (400 MHz, CD₃OD) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 4H), 9.1 (m, 1H); HPLC Purity: 98.6%; LCMS, m/z found549.5 (M-1)⁺.

N-(4-(4-(3,4-Difluorobenzoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide2,2,2-trifluoroacetate (130k)

¹H NMR (400 MHz, CD₃OD) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,8H), 8.2-8.4 (m, 4H), 9.1 (m, 1H); HPLC Purity: 99.4%; LCMS, m/z found549.3 (M-1)⁺.N-(4-(4-(2-Methylnicotinoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130l):

¹H NMR (400 MHz, CD₃OD) δ:1.4-1.6 (m, 2H), 2.1 (s, 3H), 3.0-3.8 (m, 8H),7.0-8.0 (m, 8H), 8.2-8.4 (m, 4H), 9.1 (m, 1H); HPLC Purity: 98.0%; LCMS,m/z found 530.4 (M+1)⁺.

N-(4-(4-(2-Phenylacetyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide2,2,2-trifluoroacetate (130m)

¹H NMR (400 MHz, CD₃OD) δ:1.4-1.6 (m, 2H), 1.6-2.0 (s, 2H), 3.0-3.8 (m,8H), 7.0-8.0 (m, 8H), 8.2-8.4 (m, 6H), 9.1 (m, 1H); HPLC Purity: 98.8%;LCMS, m/z found 529.1 (M+1)⁺.

N-(4-(4-(1,2,3-Thiadiazole-4-carbonyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide2,2,2-trifluoroacetate (130n)

¹H NMR (400 MHz, CD₃OD) δ:1.4-1.6 (m, 2H), 3.0-3.8 (m, 8H), 7.0-8.0 (m,6H), 8.2-8.4 (m, 4H), 9.1 (s, 1H); HPLC Purity: 98.5%; LCMS, m/z found523.1 (M+1)⁺.

N-(4-(4-(3-Phenylpropanoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130o)

¹H NMR (400 MHz, CD₃OD) δ:1.4-1.6 (m, 2H), 1.7 (t, 2H), 1.8 (t, 2H),3.0-3.8 (m, 8H), 7.0-8.0 (m, 8H), 8.2-8.4 (m, 6H), 9.1 (s, 1H); HPLCPurity: 98.2%; LCMS, m/z found 543.1 (M+1)⁺.

N-(4-(4-(2-Phenylpropanoyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130p)

¹H NMR (400 MHz, DMSOd₆) δ:1.2 (s, 3H), 1.3 (m, 2H), 3.0-3.8 (m, 8H),4.0 (m, 1H), 7.0-8.0 (m, 8H), 8.2-8.4 (m, 6H), 9.1 (s, 1H); HPLC Purity:97.1%; LCMS, m/z found 543.1 (M+1)⁺.

N-(2-Methyl-4-(4-picolinoyl-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130q)

¹H NMR (400 MHz, DMSOd₆) δ:1.2 (s, 3H), 1.3 (m, 2H), 3.0-3.8 (m, 8H),7.0-8.0 (m, 8H), 8.2-8.4 (m, 4H), 9.1 (s, 1H); HPLC Purity: 96.3%; LCMS,m/z found 530.1 (M+1)⁺.

N-(2-Hydroxy-4-(4-picolinoyl-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(130r)

¹H NMR (400 MHz, DMSOd₆) δ:1.3-1.8 (m, 2H), 3.0-3.8 (m, 8H), 5.8 (s,1H), 7.0-8.0 (m, 8H), 8.2-8.4 (m, 4H), 9.1 (s, 1H); 10.2 (s, 1H), HPLCPurity: 98.0%; LCMS, m/z found 532.2 (M+1 Synthesis of Piperazine BasedReverse Sulfonamides

General procedure for the synthesis of sulfonamide 133: To a stirredsolution of Quinoline-8-amine 131 (30.3 mmol) under nitrogen atmospherewas added pyridine (50 ml) at 0° C. and stirred for 10 min.4-(Chlorosulfonyl)benzoic acid (132, 30.3 mmol) was then added to thereaction mixture at the same temperature. The resulting mixture wasstirred for 16 hr at RT. After completion of the reaction, the solventwas removed under low pressure. The traces of pyridine were removed byco-distillation with toluene. Diethylether was added to the resultingresidue, and the solid product was filtered out and air-dried. Theresulting crude product (74%) was then to the next step without furtherpurification.

General procedure for the synthesis of sulfonamide 135: EDCI (3.8 g,19.8 mmol) and HOBT (2.67 g, 19.8 mmol) were added to a stirred solutionof the acid 133 (19.8 mmol) in anhydrous DMF. The temperature of themixture was reduced to 0° C., at which time DIPEA (11 ml, 59.45 mmol)was added under nitrogen atmosphere and the resultant solution (orsuspension) was stirred at room temperature for 30 min. Secondary amine134 (19.8 mmol) was then added at 0° C. The reaction mixture was thenbrought to room temperature and stirred overnight. After completion ofthe reaction, the reaction mixture was diluted with water and extractedwith ethyl acetate (3×70 ml). The organic layer was washed with water(3×50 ml), dried over anhydrous sodium sulfate, filtered andconcentrated over the rotary evaporator to get the crude product. Crudeproduct was purified by column chromatography (60-120 silica gel, 2%MeOH-DCM) to get pure product, Boc-135 (83%) as an off-white solid,which was subjected to the treatment with methanolic HCl (100 ml) for 2hr at RT. After the complete cleavage of Boc-group, the solvent wasremoved under low pressure, to give the crude product as an HCl salt.The aqueous solution of the salt was washed with diethylether andbasified with NaHCO₃ (pH 10). The desired product was then partitionedinto ethyl acetate, dried with anhydrous Na₂SO₄ and the solvent removedunder low pressure to get the free amine 135 as off white solid (95%).

General procedure for the synthesis of amides 136a-c: EDCI (48 mg,0.2525 mmol) and HOBT (34 mg, 0.2525 mmol) were added to a stirredsolution of the picolinic acid (0.2525 mmol) in anhydrous DMF. Thetemperature of the mixture was reduced to 0° C., at which time DIPEA(139 μl, 0.7575 mmol) was added under nitrogen atmosphere and theresultant solution (or suspension) was stirred at room temperature for30 min. Amine 135 (100 mg, 0.2525 mmol) was then added at 0° C. Thereaction mixture was then brought to room temperature and stirredovernight. After completion of the reaction, the reaction mixture wasdiluted with water and extracted with ethyl acetate (3×15 ml). Theorganic layer was washed with water (3×10 ml), dried over anhydroussodium sulfate, filtered and concentrated over the rotary evaporator toget the crude product. Crude product was purified by either by silicacolumn chromatography or preparative HPLC to obtain the pure products in55-76% yields.

4-(4-Picolinoylpiperazine-1-carbonyl)-N-(quinolin-8-yl)benzenesulfonamide(136a)

¹H NMR (400 MHz, DMSOd₆) δ:1.4-1.6 (m, 2H), 3.2-3.8 (m, 8H), 7.0-8.0 (m,10H), 8.2 (m, 1H), 8.5 (d, 2H), 8.8 (d, 2H), 10.2 (s, 1H); HPLC Purity:99.4%; LCMS, m/z found 502.1 (M+1)⁺.

4-(4-Picolinoyl-1,4-diazepane-1-carbonyl)-N-(quinolin-8-yl)benzenesulfonamide(136b)

¹H NMR (400 MHz, DMSOd₆) δ: 3.2 (m, 2H), 3.5 (m, 2H), 3.8 (m, 6H),7.0-7.4 (m, 6H), 7.6-8.0 (m, 4H), 8.2-9.0 (m, 4H), 10.2 (s, 1H); HPLCPurity: 97.8%; LCMS, m/z found 516.2 (M+1)⁺.

Synthesis of Benzyl Series—Piperazine Based Compounds with SubstitutedPhenyl Rings

Synthesis of ethyl 4-(quinoline-8-sulfonamido)benzoate (90)

To a solution of amine 88 (16 gm, 96.85 mmol) in a mixture (1:1) of DCMand pyridine, sulfonyl chloride 89 (27.56 gm, 121.07 mmol) was added atroom temperature under N2 atmosphere. The resulting mixture was allowedto stir for 16 hrs. After completion of reaction, the crude mixture wasdiluted with DCM, washed with water followed by 1N HCl. The organiclayer was then dried over Na₂SO₄ and concentrated under reduced pressureto afford product 90 in 98% yields (34 gm).

Synthesis of 4-(quinoline-8-sulfonamido)benzoic acid (91)

To a solution of sulfonamide 90 (34 gm, 95.5 mmol) in THF and water(1:1), LiOH (20 gm, 47.66 mmol) was added and the resulting mixture wasallowed to stir at 80° C. overnight. After completion of reaction, thecrude mixture was washed with EtOAc. The aqueous layer was acidifiedwith citric acid and filtered. Thus obtained solid was washed with Et₂Oand azeotroped by toluene, under reduced pressure to afford acid 91 (30gm, 95.8% yield) which was taken forward for the next step withoutfurther purification.

Synthesis of tert-butyl4-(4-(quinoline-8-sulfonamido)benzoyl)piperazine-1-carboxylate (138)

To a solution of acid 91 (2 gm, 6.09 mmol) in DMF, PyBoP(Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate) (4.75 gm, 9.14 mmol) was added at 0° C. and allowedto stir for 5 minutes. Then Boc protected piperizine/homopiperizine 137(1.13 gm, 6.09 mmol) was added to the reaction mixture at the sametemperature under N₂ atmosphere and stirred overnight at roomtemperature. After completion of reaction, mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with water,dried over Na₂SO₄, and evaporated under reduced pressure. The residuewas purified by column chromatography (silica gel, 60-120 mesh;MeOH-DCM, 2:8) to afford product 138 in 66% yield (2 gm).

Synthesis of N-(4-(piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(139)

To a solution of MeOH—HCl, Boc protected amine 138 (2 gm, 4.03 mmol) wasadded and the resulting mixture was stirred for 1 hr. After completionof reaction, solvent was removed under reduced pressure, washed withwater followed by addition of NaHCO₃ and extracted with DCM. The organiclayer was dried over Na₂SO₄ and evaporated under reduced pressure toafford product 139 (1.5 gm, 94.30% yield).

General Procedure for the Synthesis of Compound (VIII-1)-(VIII-216):

To a solution of amine 139 (0.25 mmoles) and appropriate aldehyde (0.27mmol) in DCM, acetic acid (0.2 mL) was added at room temperature and theresulting mixture was allowed to stir for 30 min. Then STAB (0.26 gm,1.26 mmol) was added to reaction mixture and the resulting mixture wasallowed to stir at 50° C. for 1 hr. After completion of reaction, thecrude mixture was diluted with DCM washed with water, dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified bycolumn chromatography (silica gel, 60-120 mesh; MeOH-DCM, 2:8) to affordproduct (VIII-1)-(VIII-216) in 32-45% yield.

N-(4-(4-benzylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-1)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H), 7.59-7.64 (m,2H), 8.03-8.28 (m, 2H), 9.18 (s, 1H), 10.4 (s, 1H); HPLC Purity: 98.7%;LCMS: 487 (M+1).

N-(4-(4-(2-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-2)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H), 7.59-8.1 (m, 4H),9.18 (s, 1H); HPLC Purity: 99.2%; LCMS: 512.3 (M+1).

N-(4-(4-(4-acetylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-3)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.6 (s, 3H), 2.40 (br d, 4H),3.38 (br d, 2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H),7.60-7.71 (m, 2H), 8.01-8.28 (m, 2H), 9.18 (s, 1H); HPLC Purity: 97.8%;LCMS: 529.2 (M+1).

N-(4-(4-(4-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-4)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H), 7.59-7.64 (m,2H), 8.03-8.28 (m, 2H), 9.18 (s, 1H); HPLC Purity: 97.8%; LCMS: 512.3(M+1).

N-(4-(4-(4-bromobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-5)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H), 7.59-7.64 (m,2H), 8.03-8.28 (m, 2H), 10.4 (s, 1H); HPLC Purity: 98.3%; LCMS: 566.1(M+1).

N-(4-(4-(3-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-6)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.8-7.04 (m, 4H), 7.1-7.2 (m, 3H), 7.59-7.64 (m, 4H),8.0-8.6 (m, 3H), 10.4 (s, 1H); HPLC Purity: 96.5%; LCMS: 522.1 (M+1).

N-(4-(4-(3-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-7)

¹H NMR (400 MHz, CDCl₃) δ: 2.40 (s, 2H), 3.9 (s, 3H), 3.68 (br s, 4H),3.4-3.6 (m, 4H), 7.06 (m, 4H), 7.18 (m, 3H), 7.25 (m, 2H), 7.42 (m, 2H),8.58 (s, 1H), 9.18 (s, 1H); HPLC Purity: 97.8%; LCMS: 517.1 (M+1).

N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-8)

¹H NMR (400 MHz, DMSO-d₆) δ:1.2 (t, 2H), 1.3 (t, 2H), 1.31-1.35 (m, 1H),2.40 (s, 2H), 3.68 (br s, 4H), 3.4-3.6 (m, 4H), 7.06 (m, 6H), 7.25-7.42(m, 3H), 9.18 (s, 1H) 10.4 (s, 1H); HPLC Purity: 97.81%; LCMS: 451.3(M+1).

N-(4-(4-butylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-9)

¹H NMR (400 MHz, DMSO-d₆) δ:1.25-1.3 (m, 2H), 1.38-1.35 (m, 2H), 1.5 (t,3H), 2.40 (s, 2H), 3.68 (br s, 4H), 3.4-3.6 (m, 4H), 7.06 (m, 6H),7.25-7.42 (m, 3H), 9.18 (s, 1H) 10.4 (s, 1H); HPLC Purity: 99.7%; LCMS:453.2 (M+1).

N-(4-(4-(pyridin-2-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-10)

¹H NMR (400 MHz, DMSO-d₆) δ: 2.5 (s, 2H), 3.68 (br s, 4H), 3.4-3.6 (m,4H), 7.0-7.4 (m, 8H), 7.3-7.4 (m, 3H), 9.18 (s, 1H), 10.4 (s, 1H); HPLCPurity: 95.8%; LCMS: 488.1 (M+1).

N-(4-(4-(2-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-11)

¹H NMR (400 MHz, DMSO-d₆) δ:2.5 (s, 2H), 3.68 (br s, 4H), 3.4-3.6 (m,4H), 7.0-7.4 (m, 6H), 7.3-7.4 (m, 4H), 8.0-8.35 (m, 3H), 9.18 (s, 1H),10.4 (s, 1H); HPLC Purity: 98.8%; LCMS: 522.1 (M+1).

N-(4-(4-(2-acetylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-12)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.6 (s, 3H), 2.40 (br d, 4H),3.38 (br d, 2H), 3.48 (d, 2H), 7.0-7.4 (m, 6H), 7.45-7.7 (m, 4H),8.0-8.4 (m, 3H), 9.18 (s, 1H), 10.4 (s, 1H); HPLC Purity: 98.3%; LCMS:529.2 (M+1).

N-(4-(4-(3-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-13)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H), 7.59-8.1 (m, 4H),10.35 (s, 1H); HPLC Purity: 99.2%; MS: 512.3 (M+1).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-14)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H), 7.59-7.64 (m,2H), 8.03-8.28 (m, 2H), 10.4 (s, 1H); HPLC Purity: 98.3%; LCMS: 522.3(M+1).

N-(4-(4-(2-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-15)

¹H NMR (400 MHz, DMSOd₆) δ: 2.5 (s, 2H), 3.68 (br s, 4H), 3.4-3.6 (m,4H), 7.0-7.4 (m, 6H), 7.3-7.4 (m, 4H), 8.0-8.35 (m, 3H), 9.18 (s, 1H),10.4 (s, 1H); HPLC Purity: 99.1%; LCMS: 512.3 (M+1).

N-(4-(4-(4-acetylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-16)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.6 (s, 3H), 2.40 (br d, 4H),3.38 (br d, 2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H),7.6-7.7 (m, 2H), 8.0-8.28 (m, 2H), 10.3 (s, 1H); HPLC Purity: 97.8%;LCMS: 529.2 (M+1).

N-(4-(4-(4-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-17)

¹H NMR (400 MHz, CDCl₃) δ: 1.8 (s, 2H), 2.40 (br d, 4H), 3.38 (br d,2H), 3.48 (d, 2H), 6.79-7.04 (m, 6H), 7.1-7.2 (m, 4H), 7.59-7.64 (m,2H), 8.03-8.28 (m, 2H), 10.3 (s, 1H); HPLC Purity: 97.8%; LCMS: 512.3(M+1).

N-(4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-18)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.31 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 6.94 (t, 2H), 7.02 (d, 2H), 7.17 (d, 2H),7.20-7.26 (m, 2H), 7.56-7.64 (m, 2H), 8.03 (d, 1H), 8.28 (d, 1H), 8.38(d, 1H), 8.58 (s, 1H), 9.18 (s, 1H); HPLC Purity: 97.62%; LCMS: 505(M-+1).

N-(4-(4-(4-bromobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-19)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.31 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 6.94 (d, 2H), 7.06 (t, 4H), 7.40 (d, 2H),7.56-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s,1H), 9.18 (s, 1H); HPLC Purity: 94.21%; LCMS: 567 (M⁺).

N-(4-(4-(3-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-20)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.31 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 7.01 (d, 2H), 7.16 (t, 3H), 7.21-7.28 (m, 5H),7.56-7.62 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s,1H), 9.18 (s, 1H); HPLC Purity: 99.41%; LCMS: 567 (M⁺+2).

N-(4-(4-(3-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-21)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.38 (br s, 2H), 3.46 (s,2H), 3.72 (br s, 2H), 3.82 (s, 3H), 6.79 (d, 1H), 6.82 (s, 2H), 7.10 (q,4H), 7.21-7.29 (m, 2H), 7.59-7.66 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H),8.38 (d, 1H), 8.56 (s, 1H), 9.18 (s, 1H); HPLC Purity: 98.26%; LCMS: 539(M⁺+23).

N-(4-(4-(3-chloro-4-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-22)

¹H NMR (400 MHz, CDCl₃) δ: 3.10 (br s, 4H), 3.84 (br s, 4H), 4.19 (s,2H), 7.16 (d, 2H), 7.21 (d, 2H), 7.28-7.34 (m, 1H), 7.44 (d, 1H),7.60-7.68 (m, 2H), 8.10 (d, 1H), 8.36 (d, 1H), 8.41 (d, 1H), 9.18 (d,1H); HPLC Purity: 96.82%; LCMS: 539 (M⁺).

N-(4-(4-(4-methoxy-2-methylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-23)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (s, 3H), 2.80 (br s, 4H), 3.80 (s, 3H),3.88 (br s, 4H), 4.20 (s, 2H), 6.78 (d, 2H), 7.10 (d, 2H), 7.20 (d, 2H),7.25 (d, 2H), 7.60-7.65 (m, 2H), 8.03 (d, 1H), 8.32 (d, 1H), 8.38 (d,1H), 9.18 (d, 1H); HPLC Purity: 96.98%; LCMS: 531 (M⁺+1).

N-(4-(4-(2-chloro-3-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-24)

¹H NMR (400 MHz, CDCl₃) δ: 2.41 (br s, 4H), 3.18 (br s, 4H), 3.81 (br s,3H), 3.98 (s, 2H), 7.02 (d, 1H), 7.13 (d, 2H), 7.18-7.22 (m, 2H), 7.30(t, 1H), 7.60-7.67 (m, 2H), 8.04 (d, 1H), 8.36 (d, 1H), 8.38 (d, 1H),9.18 (d, 1H); HPLC Purity: 99.46%; LCMS: 551 (M⁺).

N-(4-(4-(4-chloro-3-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-25)

¹H NMR (400 MHz, CDCl₃) δ:3.15 (br s, 4H), 3.84 (br s, 4H), 4.19 (s,2H), 7.13-7.24 (m, 6H), 7.48 (t, 1H), 7.61-7.68 (m, 2H), 8.10 (d, 1H),8.34 (d, 1H), 8.41 (d, 1H), 9.18 (d, 1H); HPLC Purity: 99.24%; LCMS: 539(M⁺).

N-(4-(4-(2-chloro-4-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-26)

¹H NMR (400 MHz, CDCl₃) δ: 2.37 (s, 4H), 3.21 (br s, 2H), 3.78 (br s,2H), 4.39 (s, 2H), 7.18 (d, 2H), 7.21 (d, 2H), 7.61-7.65 (m, 2H), 8.05(d, 1H), 8.36 (d, 1H), 8.41 (d, 1H), 9.18 (d, 1H); HPLC Purity: 99.56%;LCMS: 539 (M⁺).

N-(4-(4-(2,6-difluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-27)

¹H NMR (400 MHz, CDCl₃) δ: 3.07 (br s, 4H), 3.81 (s, 4H), 4.38 (s, 2H),7.06 (t, 2H), 7.12 (d, 2H), 7.18 (d, 2H), 7.54 (s, 1H), 7.60-7.64 (m,2H), 8.01 (d, 1H), 8.36 (d, 1H), 8.38 (d, 1H), 9.18 (d, 1H); HPLCPurity: 98.26%; LCMS: 523 (M⁺+1).

N-(4-(4-(2,3-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-28)

¹H NMR (400 MHz, CDCl₃) δ: 2.63 (br s, 4H), 3.57 (br s, 4H), 3.90 (d,6H), 4.18 (s, 2H), 6.98 (d, 2H), 7.00 (d, 1H), 7.14-7.19 (m, 6H),7.58-7.64 (m, 2H), 8.06 (d, 1H), 8.38 (d, 1H), 8.40 (d, 1H), 9.18 (d,1H); HPLC Purity: 99.41%; LCMS: 547 (M⁺+1).

N-(4-(4-(3,4-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-29)

¹H NMR (400 MHz, CDCl₃) δ: 2.63 (br s, 4H), 3.57 (br s, 4H), 3.90 (d,6H), 4.18 (s, 2H), 6.83 (s, 2H), 7.00 (s, 1H), 7.14 (d, 2H), 7.21 (d,2H), 7.62-7.68 (m, 2H), 8.04 (d, 1H), 8.38 (d, 1H), 8.40 (d, 1H), 9.18(d, 1H); HPLC Purity: 92.46%; LCMS: 547 (M⁺+1).

N-(4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-30)

¹H NMR (400 MHz, CDCl₃) δ: 3.09 (br s, 4H), 3.85 (s, 4H), 4.19 (s, 2H),6.94 (d, 2H), 7.06-7.21 (m, 6H), 7.40-7.44 (m, 1H), 7.62-7.68 (m, 2H),8.08 (d, 1H), 8.38 (d, 1H), 8.40 (d, 1H), 9.18 (d, 1H); HPLC Purity:98.92%; LCMS: 505 (M⁺+1).

N-(4-(4-(2-ethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-31)

¹H NMR (400 MHz, CDCl₃) δ: 1.22 (t, 3H), 2.41 (br s, 4H), 2.68 (q, 2H),3.64 (br s, 4H), 7.06 (d, 2H), 7.20 (d, 2H), 7.22-7.26 (m, 2H), 7.40 (d,2H), 7.61-7.68 (m, 2H), 8.01 (d, 1H), 8.32 (d, 1H), 8.41 (d, 1H), 9.18(d, 1H); HPLC Purity: 99.22%; LCMS: 515 (M⁺+1).

N-(4-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-32)

¹H NMR (400 MHz, CDCl₃) δ: 3.18 (br s, 4H), 3.83 (br s, 4H), 4.25 (s,2H), 7.06 (d, 2H), 7.22 (d, 2H), 7.56 (d, 2H), 7.60-7.78 (m, 4H), 8.07(d, 1H), 8.36 (d, 1H), 8.40 (d, 1H), 9.18 (s, 1H); HPLC Purity: 96.72%;LCMS: 555 (M⁺+1).

N-(4-(4-(pyridin-4-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-33)

¹H NMR (400 MHz, CDCl₃) δ: 2.40 (br s, 4H), 3.33 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 7.06 (d, 2H), 7.18 (d, 2H), 7.26 (d, 3H),7.58-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.79 (br s,2H), 9.18 (s, 1H); HPLC Purity: 97.4%; LCMS: 488.3 (M⁺+1).

N-(4-(4-(pyridin-3-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-34)

¹H NMR (400 MHz, CDCl₃) δ: 2.40 (br s, 4H), 3.33 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 7.06 (d, 2H), 7.18 (d, 2H), 7.26 (d, 3H),7.58-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.51-8.59(m, 2H), 9.18 (s, 1H); HPLC Purity: 98.50%; LCMS: 488.0 (M⁺+1).

N-(4-(4-(2-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-35)

¹H NMR (400 MHz, CDCl₃) δ: 2.42 (br d, 4H), 3.38 (br s, 2H), 3.58 (s,2H), 3.70 (br s, 2H), 3.80 (s, 3H), 6.83-6.93 (m, 2H), 7.06 (d, 2H),7.18 (d, 2H), 7.20-7.26 (m, 2H), 7.58-7.63 (m, 2H), 8.01 (d, 1H), 8.28(d, 1H), 8.38 (d, 1H), 8.51-8.59 (m, 2H), 9.18 (s, 1H); HPLC Purity:98.9%; LCMS: 517.1 (M⁺+1).

N-(4-(4-((2-chloropyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-36)

¹H NMR (400 MHz, CDCl₃) δ: 2.44 (br s, 4H), 3.41 (br s, 2H), 3.60 (s,2H), 3.74 (br s, 2H), 7.06 (d, 2H), 7.20 (d, 2H), 7.22-7.28 (m, 2H),7.59-7.66 (m, 2H), 7.81 (d, 1H), 8.01 (d, 1H), 8.35 (d, 2H), 8.39 (d,1H), 8.59 (s, 1H), 9.18 (s, 1H); HPLC Purity: 98.6%; LCMS: 522 (M⁺).

N-(4-(4-((6-chloropyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-37)

¹H NMR (400 MHz, CDCl₃) δ: 2.44 (br s, 4H), 3.41 (br s, 2H), 3.54 (s,2H), 3.74 (br s, 2H), 7.06 (d, 2H), 7.20 (d, 2H), 7.22-7.28 (m, 2H),7.59-7.66 (m, 3H), 8.01 (d, 1H), 8.35 (d, 2H), 8.39 (d, 1H), 8.59 (s,1H), 9.18 (s, 1H); HPLC Purity: 99.22%; LCMS: 522 (M⁺).

N-(4-(4-(2-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-38)

¹H NMR (400 MHz, CDCl₃) δ: 2.44 (br d, 4H), 3.41 (br s, 2H), 3.61 (s,2H), 3.74 (br s, 2H), 7.06 (d, 2H), 7.08-7.24 (m, 4H), 7.32 (d, 1H),7.39 (d, 1H), 7.59-7.7.65 (m, 2H), 8.01 (d, 1H), 8.35 (d, 1H), 8.39 (d,1H), 8.58 (s, 1H), 9.18 (s, 1H); HPLC Purity: 94.42%; LCMS: 521 (M⁺).

N-(4-(4-(2-acetylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-39)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 2.58 (s, 3H), 3.31 (br s,2H), 3.60 (s, 2H), 3.64 (br s, 2H), 7.03 (d, 2H), 7.15 (d, 2H),7.30-7.41 (m, 3H), 7.43 (d, 1H), 7.59-7.64 (m, 2H), 8.01 (d, 1H), 8.30(d, 1H), 8.38 (d, 1H), 8.56 (s, 1H), 9.18 (s, 1H); HPLC Purity: 96.32%;LCMS: 529 (M⁺+1).

N-(4-(4-(3-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-40)

¹H NMR (400 MHz, CDCl₃) δ: 2.43 (br d, 4H), 3.38 (br s, 2H), 3.68 (s,4H), 7.08 (d, 2H), 7.18 (d, 2H), 7.40 (t, 1H), 7.45-7.70 (m, 5H), 8.01(d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s, 1H), 9.18 (s, 1H); HPLC:98.2%; LCMS: 512 (M⁺+1).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-41)

¹H NMR (400 MHz, CDCl₃) δ: 2.39 (br d, 4H), 3.39 (br s, 2H), 3.50 (s,2H), 3.64 (br s, 2H), 7.06 (d, 2H), 7.17 (d, 2H), 7.40 (d, 2H), 7.44 (d,1H), 7.56-7.63 (m, 4H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56(s, 1H), 9.18 (s, 1H); HPLC Purity: 96.9%; LCMS: 521 (M⁺+1).

N-(4-(4-(2-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-42)

¹H NMR (400 MHz, CDCl₃) δ: 2.39 (br s, 4H), 3.38 (br s, 2H), 3.50 (s,2H), 3.68 (br s, 2H), 7.03 (d, 2H), 7.18 (d, 2H), 7.40 (t, 1H),7.51-7.64 (m, 4H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s,1H), 9.18 (s, 1H); HPLC Purity: 97.70%; ESMS: 512 (M⁺+1).

N-(4-(4-(4-acetylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-43)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 2.58 (s, 3H), 3.34 (br s,2H), 3.58 (s, 2H), 3.68 (br s, 2H), 7.03 (d, 2H), 7.15 (d, 2H), 7.40 (d,2H), 7.43 (d, 1H), 7.59-7.64 (m, 2H), 7.91 (d, 2H), 8.01 (d, 1H), 8.30(d, 1H), 8.38 (d, 1H), 8.56 (s, 1H), 9.18 (s, 1H); HPLC Purity: 92.23%;ESMS: 529 (M⁺+1).

N-(4-(4-(4-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-44)

¹H NMR (400 MHz, CDCl₃) δ: 2.39 (br s, 4H), 3.38 (br s, 2H), 3.52 (s,2H), 3.68 (br s, 2H), 7.03 (d, 2H), 7.18 (d, 2H), 7.40 (d, 1H),7.59-7.64 (m, 4H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s,1H), 9.18 (s, 1H); HPLC Purity: 98.71%; LCMS: 512 (M⁺+1).

N-(4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-45)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.35 (br s, 2H), 3.46 (s,2H), 3.64 (br s, 2H), 6.94 (t, 2H), 7.06 (t, 2H), 7.18 (d, 2H),7.24-7.28 (m, 2H), 7.56-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38(d, 1H), 8.56 (s, 1H), 9.18 (s, 1H); HPLC Purity: 94.7%; LCMS: 505(M⁺+1).

N-(4-(4-(4-bromobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-46)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.31 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 7.06 (d, 2H), 7.18 (t, 3H), 7.40 (d, 2H),7.56-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s,1H), 9.18 (s, 1H); HPLC Purity: 99.7%; LCMS: 567 (M⁺+2).

N-(4-(4-(3-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-47)

¹H NMR (400 MHz, CDCl₃) δ: 2.39 (br d, 4H), 3.39 (br s, 2H), 3.48 (s,2H), 3.64 (br s, 2H), 7.06 (d, 2H), 7.17 (d, 2H), 7.40 (d, 2H), 7.44 (d,1H), 7.58-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56(s, 1H), 9.18 (s, 1H); HPLC Purity: 98.98%; ESMS: 521 (M⁺+1).

N-(4-(4-(2,4-dichloro-5-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-49)

¹H NMR (400 MHz, DMSO-d6) δ: 2.39 (br s, 4H), 3.48 (br s, 4H), 3.70 (s,2H), 6.98 (s, 1H), 7.01 (s, 1H), 7.10-7.20 (m, 4H), 7.70-7.79 (m, 2H),8.28 (d, 1H), 8.43 (d, 1H), 8.55 (d, 1H), 9.18 (s, 1H), 10.41 (s, 1H);HPLC Purity: 95.42%; LCMS: 571 (M⁺).

N-(4-(4-(2-fluoro-6-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-50)

¹H NMR (400 MHz, DMSO-d6) δ: 2.39 (s, 4H), 3.42 (br s, 4H), 3.63 (s,3H), 6.56-6.62 (m, 2H), 7.10-7.19 (m, 4H), 7.70-7.79 (m, 2H), 8.28 (d,1H), 8.43 (d, 1H), 8.55 (d, 1H), 9.18 (s, 1H), 10.41 (s, 1H); HPLCPurity: 99.89%; LCMS: 521 (M⁺+1).

N-(4-(4-(2-(methylthio)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-51)

¹H NMR (400 MHz, DMSO-d6) δ: 2.35 (br s, 4H), 2.39 (s, 3H), 3.43 (s,4H), 3.61 (s, 2H), 7.10-7.19 (m, 4H), 7.26 (s, 3H), 7.30 (q, 1H),7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.43 (d, 1H), 8.55 (d, 1H), 9.18 (s,1H), 10.41 (s, 1H); HPLC Purity: 91.14%; LCMS: 533 (M⁺+1).

N-(4-(4-(2-fluoro-6-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-52)

¹H NMR (400 MHz, DMSO-d6) δ: 2.32 (br s, 4H), 3.55 (s, 3H), 3.62 (br s,4H), 3.80 (s, 2H), 6.78 (t, 1H), 6.84 (d, 1H), 7.13 (s, 4H), 7.30 (q,1H), 7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.43 (d, 1H), 8.55 (d, 1H), 9.18(s, 1H), 10.41 (s, 1H); HPLC Purity: 98.18%; LCMS: 535 (M⁺+1).

N-(4-(4-(2-(tert-butylthio)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-53)

¹H NMR (400 MHz, DMSO-d6) δ: 1.24 (s, 9H), 2.37 (br s, 4H), 3.30 (br s,4H), 3.78 (s, 2H), 7.08-7.18 (m, 4H), 7.25 (t, 1H), 7.41 (t, 1H),7.50-7.59 (m, 2H), 7.70-7.79 (m, 2H), 8.29 (d, 1H), 8.43 (d, 1H), 8.48(d, 1H), 9.18 (s, 1H), 10.41 (s, 1H); HPLC Purity: 97.92%; LCMS: 575(M⁺+1).

N-(4-(4-(3-chloro-4-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-54)

¹H NMR (400 MHz, DMSO-d6) δ: 2.29 (br s, 4H), 3.43 (s, 4H), 3.62 (s,2H), 7.06-7.18 (m, 4H), 7.25-7.39 (m, 2H), 7.46 (d, 1H), 7.70-7.79 (m,2H), 8.29 (d, 1H), 8.43 (d, 1H), 8.48 (d, 1H), 9.18 (s, 1H), 10.41 (s,1H); HPLC Purity: 96.47%; LCMS: 539 (M⁺).

N-(4-(4-(2,6-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-55)

¹H NMR (400 MHz, DMSO-d6) δ: 2.32 (br s, 4H), 3.50 (br s, 4H), 3.76 (s,6H), 3.81 (s, 2H), 6.60 (d, 2H), 7.10 (s, 3H), 7.22 (t, 1H), 7.70-7.79(m, 2H), 8.28 (d, 1H), 8.43 (d, 1H), 8.54 (d, 1H), 9.18 (s, 1H), 10.41(br s, 1H); HPLC purity: 94.09%; LCMS: 547 (M⁺+1).

N-(4-(4-(3,5-difluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-56)

¹H NMR (400 MHz, DMSO-d6) δ: 2.30 (br s, 4H), 3.45 (s, 3H), 7.01 (d,2H), 7.10-7.21 (m, 4H), 7.70-7.79 (m, 2H), 8.29 (d, 1H), 8.43 (d, 1H),8.48 (d, 1H), 9.18 (s, 1H), 10.41 (s, 1H); HPLC Purity: 96.47%; LCMS:523 (M⁺+1).

N-(4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-57)

¹H NMR (400 MHz, DMSO-d6) δ: 2.36 (br s, 4H), 3.41 (br s, 2H), 3.59 (s,2H), 7.10-7.21 (m, 6H), 7.37-7.40 (m, 1H), 7.70-7.79 (m, 2H), 8.31 (d,1H), 8.43 (d, 1H), 8.48 (d, 1H), 9.18 (s, 1H), 10.41 (s, 1H); HPLCPurity: 94.31%; LCMS: 505 (M⁺+1).

N-(4-(4-(3-fluoro-4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-58)

¹H NMR (400 MHz, DMSO-d6) δ: 2.36 (br s, 4H), 3.42 (br s, 4H), 3.59 (s,3H), 7.10-7.21 (m, 4H), 7.39 (d, 1H), 7.42 (d, 1H), 7.70-7.79 (m, 2H),8.32 (d, 1H), 8.43 (d, 1H), 8.48 (d, 1H), 9.18 (s, 1H), 10.41 (s, 1H);HPLC Purity: 96.69%; LCMS: 595 (M⁺+23).

methyl4-((4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)methyl)benzoate(VIII-59)

¹H NMR (400 MHz, DMSO-d6) δ: 2.36 (br s, 4H), 3.43 (br s, 4H), 3.59 (s,2H), 3.83 (s, 3H), 7.10-7.21 (m, 4H), 7.46 (d, 2H), 7.70-7.79 (m, 2H),7.95 (d, 2H), 8.32 (d, 1H), 8.43 (d, 1H), 8.48 (d, 1H), 9.18 (s, 1H),10.41 (s, 1H); HPLC Purity: 97.92%; LCMS: 545 (M⁺+1)

N-(4-(4-(2,5-dimethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-60)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (s, 6H), 2.41 (br s, 4H), 3.41 (br s,4H), 6.97-7.02 (m, 2H), 7.10-7.21 (m, 3H), 7.31 (s, 1H), 7.70-7.79 (m,2H), 8.29 (d, 1H), 8.43 (d, 1H), 8.56 (d, 1H), 9.18 (s, 1H), 10.41 (brs, 1H); HPLC Purity: 99.73%; LCMS: 515 (M⁺+1).

N-(4-(4-(2,4-dichlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-61)

¹H NMR (400 MHz, DMSO-d6) δ 2.38 (br s, 4H), 3.41 (br s, 4H), 3.59 (s,2H), 7.10 (q, 4H), 7.39 (d, 1H), 7.43 (d, 1H), 7.59 (s, 1H), 7.70-7.79(m, 2H), 8.29 (d, 1H), 8.43 (d, 1H), 8.56 (d, 1H), 9.18 (s, 1H), 10.41(br s, 1H); HPLC Purity: 99.34%; LCMS: 555 (M⁺).

N-(4-(4-(4-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-62)

¹H NMR (400 MHz, DMSO-d6) δ: 2.32 (br s, 4H), 3.52 (br s, 4H), 3.79 (s,2H), 6.81 (d, 2H), 7.10-7.21 (m, 5H), 7.31 (s, 1H), 7.70-7.79 (m, 2H),8.28 (d, 1H), 8.43 (d, 1H), 8.56 (d, 1H), 9.18 (s, 1H), 10.41 (br s,1H); HPLC Purity: 96.49%; LCMS: 539 (M⁺+23).

N-(4-(4-(5-chloro-2-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-63)

¹H NMR (400 MHz, DMSO-d6) δ: 2.38 (br s, 4H), 3.59 (s, 4H), 3.62 (s,2H), 6.79 (d, 2H), 7.06-7.21 (m, 6H), 7.70-7.81 (m, 2H), 8.31 (d, 1H),8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s, 1H), 9.18 (s, 1H), 10.41 (s, 1H);HPLC Purity: 97.02%; LCMS: 537 (M⁺).

N-(4-(4-(4-methylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-64)

¹H NMR (400 MHz, DMSO-d6) δ: 2.30 (s, 4H), 3.42 (s, 4H), 3.46 (s, 2H),7.06-7.20 (m, 8H), 7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.43 (d, 1H), 8.56(d, 1H), 9.18 (s, 1H), 10.41 (br s, 1H); HPLC Purity: 98.59%; LCMS: 501(M⁺+1).

N-(4-(4-(3-chloro-4-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-65)

¹H NMR (400 MHz, DMSO-d6) δ: 2.30 (br s, 4H), 3.45 (br s, 6H), 3.81 (s,3H), 7.04-7.21 (m, 6H), 7.31 (s, 1H), 7.70-7.79 (m, 2H), 8.28 (d, 1H),8.43 (d, 1H), 8.56 (d, 1H), 9.18 (s, 1H), 10.41 (br s, 1H); HPLC Purity:99.70%; LCMS: 551 (M⁺).2-methoxy-4-((4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)methyl)phenylacetate (VIII-66):

¹H NMR (400 MHz, DMSO-d6) δ:2.22 (s, 3H), 2.38 (br s, 4H), 3.31 (br s,2H), 3.51 (s, 4H), 3.80 (s, 3H), 6.89 (d, 1H), 7.04 (d, 2H), 7.10-7.23(m, 4H), 7.71-7.79 (m, 2H), 8.31 (d, 1H), 8.45 (d, 1H), 8.56 (d, 1H),9.18 (d, 1H), 10.42 (s, 1H); HPLC Purity: 91.90%; LCMS: 575 (M⁺+1).

N-(4-(4-(4-cyanobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-67)

¹H NMR (400 MHz, DMSO-d6) δ: 2.23 (br s, 4H), 3.41 (br s, 2H), 3.54 (s,2H), 7.06 (q, 4H), 7.22 (s, 2H), 7.62-7.76 (m, 4H), 8.22 (d, 1H), 8.38(d, 1H), 8.44 (d, 1H), 9.08 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.87%;MS: 512 (M⁺+1).

N-(4-(4-(3,5-dichlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-68)

¹H NMR (400 MHz, DMSO-d6) δ: 2.24 (br s, 4H), 3.41 (br s, 4H), 3.44 (s,2H), 7.08 (q, 3H), 7.30 (2H), 7.41 (s, 1H), 7.60-7.66 (m, 2H), 8.21 (d,1H), 8.38 (d, 1H), 8.44 (d, 1H), 9.08 (s, 1H), 10.38 (s, 1H); HPLCPurity: 99.83%; LCMS: 555 (M⁺).

N-(4-(4-(2,5-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-69)

¹H NMR (400 MHz, DMSO-d6) δ: 2.23 (br s, 4H), 3.40 (s, 4H), 3.61 (d,6H), 3.72 (s, 2H), 6.82 (d, 3H), 7.02-7.10 (m, 4H), 7.60-7.68 (m, 2H),8.22 (d, 1H), 8.38 (d, 1H), 8.44 (d, 1H), 9.08 (s, 1H), 10.40 (s, 1H);HPLC Purity: 98.63%; LCMS: 547 (M⁺+1).

N-(4-(4-(2-hydroxy-6-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-70)

¹H NMR (400 MHz, DMSO-d6) δ: 2.36 (br s, 4H), 3.54 (s, 4H), 3.61 (s,2H), 3.64 (s, 3H), 6.36 (d, 1H), 7.00-7.10 (m, 5H), 7.60-7.68 (m, 2H),8.20 (d, 1H), 8.38 (d, 1H), 8.44 (d, 1H), 9.08 (s, 1H), 10.40 (s, 1H);HPLC Purity: 98.03%; LCMS: 533 (M⁺+1).

N-(4-(4-(5-chloro-2-hydroxy-4-methylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-71)

¹H NMR (400 MHz, DMSO-d6) δ: 2.18 (s, 3H), 2.30 (br s, 4H), 3.41 (s,4H), 3.46 (s, 2H), 6.68 (s, 1H), 7.10-7.19 (m, 4H), 7.65-7.78 (m, 2H),8.24 (d, 1H), 8.41 (d, 1H), 8.51 (d, 1H), 9.12 (s, 1H), 10.40 (s, 1H);HPLC Purity: 96.25%; LCMS: 551 (M⁺).

N-(4-(4-(4-(hex-1-ynyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-72)

¹H NMR (400 MHz, DMSO-d6) δ:0.93 (t, 3H), 1.38-1.41 (m, 4H), 2.22 (br s,6H), 2.38 (t, 2H), 2.80 (s, 3H), 3.44 (s, 2H), 6.22 (d, 1H), 7.00-7.12(m, 4H), 7.22 (dd, 2H), 7.62-7.70 (m, 2H), 8.24 (d, 1H), 8.38 (d, 1H),8.44 (d, 1H), 9.08 (s, 1H), 9.60 (br s, 1H), 10.36 (s, 1H); HPLCPpurity:99.84%; LCMS: 567 (M⁺+1).

N-(4-(4-(2-ethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-73)

¹H NMR (400 MHz, DMSO-d6) δ:1.12 (t, 3H), 2.23 (br s, 4H), 2.62 (q, 2H),3.40 (s, 2H), 3.43 (br s, 4H), 7.04-7.20 (m, 5H), 7.65-7.70 (m, 2H),8.25 (d, 1H), 8.41 (d, 1H), 8.50 (d, 1H), 9.10 (s, 1H), 10.40 (s, 1H);HPLC Purity: 98.83%; LCMS: 515 (M⁺+1).

N-(4-(4-(4-(dimethylamino)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-74)

¹H NMR (400 MHz, DMSO-d6) δ: 2.21 (br s, 4H), 2.81 (s, 6H), 3.41 (br s,6H), 6.61 (d, 2H), 7.01-7.11 (m, 6H), 7.48 (d, 2H), 7.63-7.70 (m, 2H),8.22 (d, 1H), 8.38 (d, 1H), 8.45 (d, 1H), 9.08 (s, 1H), 10.40 (br s,1H); HPLC Purity: 96.86%; LCMS: 552 (M⁺+23).

N-(4-(4-(2-hydroxy-3-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-75)

¹H NMR (400 MHz, DMSO-d6) δ: 2.30 (br s, 4H), 3.41 (br s, 4H), 3.54 (s,2H), 3.75 (s, 3H), 6.66 (s, 2H), 6.80 (d, 1H), 7.20 (q, 4H), 7.48 (d,2H), 7.62-7.70 (m, 2H), 8.24 (d, 1H), 8.38 (d, 1H), 8.48 (d, 1H), 9.10(s, 1H), 10.40 (s, 1H); HPLC Purity: 99.76%; LCMS: 555 (M⁺+23).

N-(4-(4-(3,4-dichlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-76)

¹H NMR (400 MHz, DMSO-d6) δ: 2.24 (br s, 4H), 3.41 (s, 4H), 3.45 (s,2H), 7.05 (q, 4H), 7.24 (d, 1H), 7.52-7.58 (m, 2H), 7.66-7.74 (m, 4H),8.24 (d, 1H), 8.38 (d, 1H), 8.48 (d, 1H), 9.10 (s, 1H), 10.40 (br s,1H); HPLC Purity: 97.35%; LCMS: 555 (M⁺).

N-(4-(4-(3-(2-hydroxyethoxy)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-77)

¹H NMR (400 MHz, DMSO-d6) δ: 2.23 (br s, 4H), 3.40 (s, 4H), 3.69 (q,2H), 3.98 (t, 2H), 4.78 (s, 2H), 6.79-7.01 (m, 3H), 7.12 (q, 4H), 7.18(t, 1H), 7.62-7.70 (m, 2H), 8.26 (d, 1H), 8.38 (d, 1H), 8.46 (s, 1H),9.10 (s, 1H), 10.38 (s, 1H); HPLC Purity: 97.11%; LCMS: 547 (M⁺+1).

N-(4-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-78)

¹H NMR (400 MHz, DMSO-d6) δ: 2.24 (br s, 4H), 3.46 (br s, 4H), 3.55 (s,2H), 7.08 (q, 4H), 7.48 (d, 2H), 7.60-7.70 (m, 4H), 8.24 (d, 1H), 8.38(d, 1H), 8.48 (d, 1H), 9.10 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.28%;LCMS: 555 (M⁺+1).

N-(4-(4-(2,4,5-trimethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-79)

¹H NMR (400 MHz, DMSO-d6) δ: 2.12 (s, 6H), 2.20 (s, 3H), 2.23 (br s,4H), 3.41 (br s, 4H), 3.46 (s, 2H), 6.88 (d, 2H), 7.08 (q, 4H),7.62-7.70 (m, 2H), 8.28 (d, 1H), 8.40 (d, 1H), 8.48 (d, 1H), 9.10 (s,1H), 10.40 (s, 1H); HPLC Purity: 99.58%; LCMS: 529 (M⁺+1).

N-(4-(4-(4-(pentyloxy)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-80)

¹H NMR (400 MHz, DMSO-d6) δ: 0.85 (t, 3H), 1.25-1.39 (m, 4H), 1.65(pentet, 2H), 2.22 (br s, 4H), 3.38 (s, 4H), 3.41 (s, 2H), 3.90 (t, 2H),6.80 (d, 2H), 7.08-7.14 (m, 6H), 7.68-7.75 (m, 2H), 8.28 (d, 1H), 8.40(d, 1H), 8.50 (s, 1H), 9.10 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.80%;LCMS: 573 (M⁺+1).

N-(4-(4-(2-methylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-81)

¹H NMR (400 MHz, DMSO-d6) δ:2.24 (s, 3H), 2.36 (br s, 4H), 3.38 (s, 4H),3.40 (s, 2H), 7.05-7.20 (m, 6H), 7.65-7.74 (m, 2H), 8.26 (d, 1H), 8.39(d, 1H), 8.46 (s, 1H), 9.10 (s, 1H), 10.40 (s, 1H); HPLC Purity: 98.75%;LCMS: 501 (M⁺+1).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-82)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.31 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 6.94 (d, 2H), 7.06 (t, 4H), 7.40 (d, 2H),7.56-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (m, 2H), 9.18 (s, 1H); HPLCpurity: 97.61%; LCMS: 522.0 (M⁺).

N-(4-(4-(3-propoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-83)

¹H NMR (400 MHz, DMSO-d6) δ: 0.97 (t, 3H), 1.70 (q, 2H), 2.32 (s, 4H),3.41 (br s, 4H), 3.90 (t, 2H), 4.22 (br s, 2H), 6.99 (d, 2H), 7.17 (dd,4H), 7.36 (t, 1H), 7.68-7.74 (m, 2H), 8.28 (d, 1H), 8.39 (d, 1H), 8.50(d, 1H), 9.16 (s, 1H), 10.50 (s, 1H); HPLC Purity: 99.57%; LCMS: 545(M-+1).

N-(4-(4-(2-propoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-84)

¹H NMR (400 MHz, DMSO-d6) δ: 0.97 (t, 3H), 1.70 (q, 2H), 2.36 (br s,4H), 3.42 (br s, 4H), 3.90 (t, 2H), 4.22 (br s, 2H), 6.99 (d, 2H), 7.17(dd, 4H), 7.40 (br s, 1H), 7.68-7.74 (m, 2H), 8.28 (d, 1H), 8.39 (d,1H), 8.50 (d, 1H), 9.16 (s, 1H), 10.50 (s, 1H); HPLC Purity: 99.12%;LCMS: 545 (M-+1).

N-(4-(4-(2-isopropoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-85)

¹H NMR (400 MHz, DMSO-d6) δ:1.37 (d, 6H), 3.12 (br s, 3H), 4.25 (br s,2H), 4.71-4.75 (m, 1H), 7.01 (t, 2H), 7.17 (d, 2H), 7.22 (d, 2H), 7.42(br s, 2H), 7.70-7.79 (m, 2H), 8.30 (d, 1H), 8.42 (d, 1H), 8.51 (d, 1H),9.14 (s, 1H), 9.50 (br s, 1H), 10.55 (s, 1H); HPLC Purity: 99.17%; LCMS:545 (M⁺+1).

N-(4-(4-(3-isopropoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-86)

¹H NMR (400 MHz, DMSO-d6) δ:1.29 (d, 6H), 2.36 (br s, 4H), 3.02 (br s,4H), 4.25 (s, 2H), 4.62 (sextet, 1H), 6.99-7.09 (m, 3H), 7.20 (dd, 4H),7.39 (t, 1H), 7.70-7.79 (m, 2H), 8.30 (d, 1H), 8.42 (d, 1H), 8.51 (d,1H), 9.14 (s, 1H), 9.79 (br s, 1H), 10.57 (s, 1H); HPLC Purity: 99.11%;LCMS: 545 (M⁺+1).

N-(4-(4-(3-butoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-87)

¹H NMR (400 MHz, DMSO-d6) δ: 0.90 (t, 3H), 1.21 (sextet, 2H), 1.64(pentet, 2H), 2.31 (br s, 4H), 3.36 (br s, 4H), 3.92 (t, 2H), 4.23 (s,2H), 6.93-7.01 (m, 2H), 7.17 (q, 4H), 7.31 (s, 2H), 7.63-7.74 (m, 2H),8.28 (d, 1H), 8.40 (d, 1H), 8.51 (d, 1H), 9.10 (s, 1H), 9.50 (br s, 1H),10.55 (s, 1H); HPLC Purity: 99.06%; LCMS: 559 (M⁺+1).

N-(4-(4-(2-isopropylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-88)

¹H NMR (400 MHz, DMSO-d6) δ: 1.17 (d, 6H), 3.10 (br s, 4H), 3.21 (br s,4H), 4.35 (s, 2H), 4.62 (sextate, 1H), 7.18 (dd, 4H), 7.17 (d, 2H), 7.21(br s, 1H), 7.20 (s, 2H), 7.68-7.74 (m, 2H), 8.28 (d, 1H), 8.40 (d, 1H),8.51 (d, 1H), 9.14 (s, 1H), 9.50 (br s, 1H), 10.55 (s, 1H); HPLC Purity:99.16%; LCMS: 529 (M⁺+1).

N-(4-(4-(4-isobutoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-89)

¹H NMR (400 MHz, DMSO-d6) δ: 0.96 (d, 6H), 2.00 (septet, 1H), 2.99 (brs, 2H), 3.18 (br s, 2H), 3.22 (br s, 2H), 3.70 (d, 2H), 4.20 (s, 2H),6.99 (d, 2H), 7.18 (dd, 4H), 7.35 (d, 2H), 7.65-7.73 (m, 2H), 8.28 (d,1H), 8.40 (d, 1H), 8.51 (d, 1H), 9.10 (s, 1H), 9.50 (br s, 1H), 10.55(s, 1H); HPLC Purity: 99.06%; LCMS: 559 (M⁺+1).

N-(4-(4-(2-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-90)

¹H NMR (400 MHz, DMSO-d6) δ:1.21 (d, 3H), 2.99 (br s, 3H), 3.21 (br s,2H), 7.17 (d, 4H), 7.21-7.35 (m, 4H), 7.63-7.74 (m, 2H), 8.28 (d, 1H),8.40 (d, 1H), 8.51 (d, 1H), 9.10 (s, 1H), 9.24 (br s, 1H), 10.55 (s,1H); HPLC Purity: 99.88%; LCMS: 515 (M⁺+1).

N-(4-(4-(4-methoxy-3-methylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-91)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (s, 3H), 3.02 (br s, 2H), 3.20 (br s,2H), 3.30 (br s, 4H), 3.80 (s, 3H), 4.21 (s, 2H), 7.01 (d, 1H),7.16-7.29 (m, 4H), 7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.44 (d, 1H), 8.57(d, 1H), 9.14 (s, 1H), 9.78 (br s, 1H), 10.55 (s, 1H); HPLC Purity:99.86%; LCMS: 531 (M⁺+1).

N-(4-(4-(4-isopropylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-92)

¹H NMR (400 MHz, DMSO-d6) δ: 1.20 (d, 6H), 2.31 (br s, 4H), 2.95(pentet, 1H), 3.42 (br s, 4H), 4.22 (br s, 2H), 7.20 (dd, 4H), 7.39 (q,4H), 7.70-7.78 (m, 2H), 8.28 (d, 1H), 8.46 (d, 1H), 8.53 (d, 1H), 9.14(s, 1H), 9.60 (br s, 1H), 10.58 (s, 1H); HPLC Purity: 97.92%; LCMS: 529(M⁺+1).

N-(4-(4-(2,6-difluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamidecompound(VIII-93)

¹H NMR (400 MHz, DMSO-d6) δ: 2.31 (br s, 4H), 3.44 (br s, 4H), 3.61 (s,2H), 7.02-7.26 (m, 5H), 7.56 (br s, 1H), 7.70-7.78 (m, 2H), 8.28 (d,1H), 8.43 (d, 1H), 8.50 (d, 1H), 9.14 (s, 1H), 10.42 (s, 1H); HPLCPurity: 99.64%; LCMS: 523 (M⁺+1).

N-(4-(4-(4-butylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-94)

¹H NMR (400 MHz, DMSO-d6) δ: 0.85 (t, 3H), 1.25 (sextet, 2H), 1.32(pentet, 2H), 2.59 (t, 2H), 3.01 (br s, 4H), 3.12 (br s, 2H), 3.22 (brs, 2H), 4.21 (s, (2H), 7.11 (d, 2H), 7.21 (d, 2H), 7.25 (d, 2H), 7.30(d, 2H), 7.63-7.71 (m, 2H), 8.28 (d, 1H), 8.40 (d, 1H), 8.51 (d, 1H),9.10 (s, 1H), 9.78 (br s, 1H), 10.50 (s, 1H); HPLC Purity: 99.98%; LCMS:543 (M⁺+1).

N-(4-(4-(2,6-dimethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-95)

¹H NMR (400 MHz, DMSO-d6) δ: 2.25 (s, 6H), 2.41 (br s, 4H), 3.02 (br s,2H), 3.20 (br s, 2H), 4.21 (br s, 2H), 7.05 (d, 3H), 7.17 (d, 2H), 7.24(d, 2H), 7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.44 (d, 1H), 8.57 (d, 1H),9.14 (s, 1H), 9.78 (br s, 1H), 10.55 (s, 1H); HPLC Purity: 98.76%; LCMS:515 (M⁺+1).

N-(4-(4-(3,5-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-96)

¹H NMR (400 MHz, DMSO-d6) δ: 2.32 (br s, 4H), 3.44 (br s, 4H), 3.72 (d,6H), 4.19 (s, 2H), 6.59 (d, 1H), 7.18 (dd, 4H), 7.69-7.75 (m, 2H), 8.28(d, 1H), 8.42 (d, 1H), 8.50 (d, 1H), 9.14 (s, 1H), 9.78 (br s, 1H),10.51 (s, 1H); HPLC Purity: 93.00%; LCMS: 547 (M⁺+1).

N-(4-(4-(4-chloro-2-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-97)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.46 (br s, 4H), 3.77 (s,3H), 4.40 (s, 2H), 7.22 (q, 4H), 7.34-7.44 (m, 2H), 7.55 (t, 1H),7.63-7.70 (m, 2H), 8.20 (d, 1H), 8.42 (d, 2H), 9.14 (s, 1H); HPLCPurity: 98.85%; LCMS: 539 (M⁺).

N-(4-(4-(4-ethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-98)

¹H NMR (400 MHz, DMSO-d6) δ:1.23 (t, 2H), 4.00 (q, 2H), 4.20 (s, 2H),6.97 (d, 2H), 7.17 (dd, 4H), 7.36 (d, 1H), 7.69-7.75 (m, 2H), 8.28 (d,1H), 8.41 (d, 1H), 8.51 (d, 1H), 9.10 (s, 1H), 9.50 (br s, 1H), 10.50(s, 1H); HPLC Purity: 96.83%; LCMS: 531 (M⁺+1).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-99)

¹H NMR (400 MHz, CD₃OD) δ: 2.34 (br s, 4H), 3.23 (br s, 2H), 3.62 (br s,2H), 4.30 (s, 2H), 7.16-7.20 (m, 4H), 7.37-7.57 (m, 4H), 7.79-7.84 (m,2H), 8.15 (d, 1H), 8.40 (d, 1H), 9.10 (s, 1H), 9.50 (br s, 1H); HPLCPurity: 99.75%; LCMS: 521 (M⁺).

N-(4-(4-(2,3-dichlorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-100)

¹H NMR (400 MHz, CD₃OD) δ: 2.32 (br s, 4H), 3.62 (br s, 4H), 3.81 (s,2H), 7.21 (q, 4H), 7.42 (t, 2H), 7.58 (d, 2H), 7.61-7.72 (m, 2H), 8.18(d, 1H), 8.41 (d, 1H), 9.18 (s, 1H); HPLC Purity: 99.15%; LCMS: 555(M⁺+1).

N-(4-(4-(2-hydroxy-5-methylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-101)

¹H NMR (400 MHz, CD₃OD-d6) δ: 2.08 (s, 3H), 2.22 (s, 4H), 3.32 (s, 4H),3.72 (s, 2H), 4.21 (s, 1H), 6.80 (d, 1H), 7.10 (s, 2H), 7.18-7.25 (m,3H), 7.61-7.68 (m, 2H), 8.18 (d, 1H), 8.40 (d, 2H), 9.14 (s, 1H); HPLCPurity: 98.02%; LCMS: 517 (M⁺+1).

N-(4-(4-(5-fluoro-2-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-102)

¹H NMR (400 MHz, DMSOd₆) δ: 2.30 (br s, 4H), 3.31 (br s, 4H), 3.72 (s,2H), 6.90-6.95 (m, 3H), 7.04-7.18 (m, 2H), 7.20-7.25 (m, 3H), 7.60-7.65(m, 2H), 8.41 (d, 2H), 9.10 (s, 1H); HPLC Purity: 98.95%; LCMS: 521(M⁺+1).

N-(4-(4-(2,4-difluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(103)

¹H NMR (400 MHz, DMSOd₆) δ: 2.36 (br s, 4H), 3.3 (br s, 4H), 3.7 (s,2H), 7.05-7.22 (m, 5H), 7.55 (d, 2H), 7.60-7.65 (m, 2H), 8.18 (d, 1H),8.40 (d, 2H), 9.10 (s, 1H); HPLC Purity: 99.24%; LCMS: 523.1 (M⁺+1).

N-(4-(4-(3,5-dichloro-2-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-104)

¹H NMR (400 MHz, DMSOd₆) δ: 2.37 (br s, 4H), 3.32 (br s, 4H), 3.71 (s,2H), 4.2 (s, 1H), 7.19-7.23 (m, 4H), 7.39 (s, 1H), 7.56 (s, 1H),7.62-7.68 (m, 2H), 8.18 (d, 2H), 8.40 (d, 1H), 9.13 (s, 1H); HPLCPurity: 99.95%; LCMS: 572.3 (M⁺+1).

N-(4-(4-(2,3-dihydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-105)

¹H NMR (400 MHz, DMSOd₆) δ: 2.30 (br s, 4H), 3.32 (br s, 4H), 3.76 (s,2H), 4.2 (br s, 2H), 7.19-7.23 (m, 4H), 7.39 (s, 1H), 7.56 (s, 1H),7.62-7.68 (m, 3H), 8.18 (d, 2H), 8.40 (d, 1H), 9.13 (s, 1H); HPLCPurity: 91.9%; LCMS: 519.1 (M⁺+1).

N-(4-(4-(3-hydroxy-4-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-106)

¹H NMR (400 MHz, DMSOd₆) δ: 3.19 (br s, 4H), 3.3-3.6 (m, 4H), 3.7 (s,2H), 3.81 (s, 3H), 6.85 (d, 2H), 6.97 (d, 1H), 7.18-7.24 (m, 5H),7.60-7.66 (m, 2H), 8.18 (d, 1H), 8.41 (d, 1H), 9.13 (s, 1H); HPLCPurity: 97.5%; LCMS: 533.1 (M⁺+1).

N-(4-(4-(2-(difluoromethoxy)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-107)

¹H NMR (400 MHz, DMSOd₆) δ: 2.7 (s, 1H), 3.19 (br s, 4H), 3.3-3.6 (m,4H), 3.7 (s, 2H), 6.97-7.0 (m, 4H), 7.18-7.24 (m, 5H), 7.60-7.66 (m,2H), 8.18 (d, 1H), 8.41 (d, 1H), 9.13 (s, 1H); HPLC Purity: 99.4%; LCMS:553.1 (M⁺+1).

N-(4-(4-(2-ethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-108)

¹H NMR (400 MHz, DMSOd₆) δ:1.89 (t, 3H), 3.19 (br s, 4H), 3.3-3.6 (m,4H), 3.7 (s, 2H), 3.91 (q, 2H), 6.97-7.0 (m, 4H), 7.18-7.24 (m, 5H),7.60-7.66 (m, 2H), 8.18 (d, 1H), 8.41 (d, 1H), 9.13 (s, 1H); HPLCPurity: 96.2%; LCMS: 553.1 (M⁺+1).

N-(4-(4-(4-hydroxy-3,5-dimethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-109)

¹H NMR (400 MHz, DMSOd₆) δ: 2.2 (s, 6H), 3.19 (br s, 4H), 3.3-3.6 (m,4H), 3.7 (s, 2H), 6.97-7.0 (m, 4H), 7.18-7.24 (m, 3H), 7.60-7.66 (m,2H), 8.18 (d, 1H), 8.41 (d, 1H), 9.13 (s, 1H); HPLC Purity: 98.4%; LCMS:531.1 (M⁺+1).

N-(4-(4-(3-ethoxy-4-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-110)

¹H NMR (400 MHz, CDCl₃) δ:1.41 (t, 3H), 2.42 (br s, 4H), 3.25-3.95 (m,4H), 3.42 (q, 2H), 3.60 (br s, 2H), 4.21 (s, 1H), 6.75 (s, 2H), 6.90 (s,1H), 7.19 (s, 4H), 7.62-7.67 (m, 2H), 8.18 (d, 1H), 8.40 (d, 2H), 9.18(s, 1H); HPLC Purity: 99.29%; LCMS: 546.1 (M⁺+1).

N-(4-(4-(4-(tert-butyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-111)

¹H NMR (400 MHz, CD₃OD) δ: 1.30 (s, 9H), 2.56 (br s, 4H), 3.30 (br s,4H), 3.68 (s, 2H), 7.20 (dd, 4H), 7.45 (dd, 4H), 7.70-7.80 (m, 2H), 8.45(d, 2H), 8.55 (d, 1H), 9.18 (s, 1H), 10.54 (s, 1H); HPLC Purity: 98.47%;LCMS: 543.0 (M⁺+1).

N-(4-(4-(5-fluoro-2-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-112)

¹H NMR (400 MHz, CDCl₃) δ: 2.45 (br s, 4H), 3.2-3.6 (m, 4H), 3.70 (s,2H), 7.20 (s, 4H), 7.59-7.74 (m, 4H), 8.18 (d, 2H), 8.40 (m, 2H), 9.16(s, 1H); HPLC Purity: 99.35%; LCMS: 573.1 (M⁺+1).

N-(4-(4-(4-chloro-2-fluoro-5-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-113)

¹H NMR (400 MHz, CD₃OD) δ: 2.91 (br s, 4H), 3.77 (br s, 4H), 3.92 (s,2H), 4.01 (s, 3H), 7.20-7.25 (m, 4H), 7.40 (d, 1H), 7.62-7.68 (m, 3H),8.18 (d, 1H), 8.41 (d, 2H), 9.13 (s, 1H); HPLC Purity: 99.42%; LCMS: 569(M⁺+1).

N-(4-((4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)methyl)phenyl)acetamide(VIII-114)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 3.01 (br s, 4H), 3.20 (br s,2H), 3.30 (br s, 2H), 4.24 (s, 2H), 7.20 (dd, 4H), 7.40 (d, 2H), 7.65(d, 2H), 7.70-7.80 (m, 2H), 8.30 (d, 1H), 8.45 (d, 1H), 8.52 (d, 1H),9.18 (s, 1H), 10.60 (s, 1H); HPLC Purity: 95.84%; LCMS: 544.1 (M⁺+1).

N-(4-(4-(2-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-115)

¹H NMR (400 MHz, CD₃OD-d6) δ: 3.01 (br s, 4H), 3.20 (br s, 2H), 3.30 (brs, 2H), 3.82 (s, 2H), 7.02-7.20 (m, 5H), 7.24-7.41 (m, 2H), 7.61-7.67(m, 2H), 8.18 (d, 1H), 8.41 (t, 2H), 9.12 (s, 1H); HPLC Purity: 99.03%;LCMS: 505 (M⁺+1).

N-(4-(4-(2,3-difluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-116)

¹H NMR (400 MHz, CD₃OD-d6) δ: 3.01 (br s, 4H), 3.20 (br s, 2H), 3.30 (brs, 2H), 4.24 (s, 2H), 7.16-7.34 (m, 6H), 7.39-7.47 (m, 2H), 7.61-7.67(m, 2H), 8.18 (d, 1H), 8.41 (d, 1H), 9.12 (s, 1H); HPLC Purity: 97.11%;LCMS: 523.2 (M⁺+1).

N-(4-(4-(2-hydroxy-4,6-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-117)

¹H NMR (400 MHz, CDCl₃) δ: 3.15 (br s, 2H), 3.2-3.6 (br s, 6H), 3.39 (brs, 2H), 3.78 (s, 3H), 3.81 (s, 3H), 6.17 (d, 2H), 7.22 (q, 4H),7.62-7.68 (m, 2H), 8.18 (d, 1H), 8.41 (d, 1H), 9.17 (s, 1H); HPLCPurity: 97.92%; LCMS: 563 (M⁺).

N-(4-(4-(3,5-dichloro-4-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-118)

¹H NMR (400 MHz, DMSO-d6) δ: 3.04 (br s, 2H), 3.30 (br s, 4H), 4.12 (s,4H), 4.2 (s, 1H), 7.21 (dd, 4H), 7.27 (s, 1H), 7.50 (s, 2H), 7.69-7.78(m, 2H), 8.30 (d, 1H), 8.50 (d, 2H), 10.59 (s, 1H), HPLC Purity: 93.26%;LCMS: 571.3 (M⁺).

N-(4-(4-(2,6-dimethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-119)

¹H NMR (400 MHz, DMSO-d6) δ: 2.44 (s, 6H), 3.34 (s, 6H), 3.39 (br s,2H), 4.45 (s, 2H), 7.19-7.30 (m, 6H), 7.63-7.70 (m, 3H), 8.20 (d, 1H),8.42 (d, 2H), 9.18 (s, 1H); HPLC Purity: 98.10%; LCMS: 515 (M⁺+1).

N-(4-(4-(3,4-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-120)

¹H NMR (400 MHz, CD₃OD) δ: 3.4-3.6 (br s, 2H), 3.85 (d, 6H), 4.1 (s,6H), 4.29 (s, 2H), 7.02 (d, 3H), 7.21-7.27 (m, 4H), 7.63-7.72 (m, 2H),8.20 (d, 1H), 8.42 (d, 1H), 9.14 (s, 1H); HPLC Purity: 99.44%; LCMS: 547(M⁺+1).

N-(4-(4-(3-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-121)

¹H NMR (400 MHz, CD₃OD) δ: 2.81 (br s, 4H), 3.20 (br s, 4H), 3.78 (s,3H), 4.25 (s, 2H), 7.01 (t, 2H), 7.20 (t, 3H), 7.39 (t, 1H), 7.61-7.67(m, 2H), 8.18 (d, 1H), 8.41 (d, 2H), 9.14 (s, 1H); HPLC Purity: 97.82%;LCMS: 517 (M⁺+1).

N-(4-(4-(4-propoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-122)

¹H NMR (400 MHz, CD₃OD) δ: 1.01 (t, 3H), 1.78 (sextet, 2H), 3.2-3.85 (brs, 4H), 3.9-4.0 (br s, 4H), 3.92 (t, 2H), 4.22 (s, 2H), 6.97 (d, 2H),7.21 (q, 4H), 7.38 (d, 2H), 7.61-7.67 (m, 2H), 8.18 (d, 1H), 8.40 (d,2H), 9.10 (s, 1H); HPLC Purity: 98.67%; LCMS: 545 (M⁺+1).

N-(4-(4-phenethylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-123)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (t, 2H), 2.20 (t, 2H), 2.8 (br s, 2H),3.2-3.89 (m, 6H), 7.04-7.32 (m, 4H), 7.59-7.63 (m, 6H), 8.01 (d, 1H),8.25 (dd, 2H), 8.41 (d, 1H), 9.18 (s, 1H); HPLC Purity: 99.43%; LCMS:501 (M⁺+1).

N-(4-(4-(2,3,4-trimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-124)

¹H NMR (400 MHz, DMSO-d6) δ: 3.01 (br s, 2H), 3.32-3.71 (m, 6H), 3.78(s, 3H), 3.84 (s, 3H), 3.86 (s, 3H), 4.22 (br s, 2H), 6.89 (d, 1H), 7.18(d, 3H), 7.25 (d, 2H), 7.72-7.80 (m, 2H), 8.30 (d, 1H), 8.45 (d, 1H),8.55 (d, 1H), 9.18 (d, 1H), 10.59 (s, 1H); HPLC Purity: 99.84%; LCMS:577 (M⁺+1).

N-(4-(4-(4-hydroxy-3,5-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-125)

¹H NMR (400 MHz, DMSO-d6) δ: 3.01 (br s, 2H), 3.21 (br s, 2H), 3.3-3.7(m, 6H), 3.79 (s, 6H), 6.75 (s, 2H), 7.20 (dd, 4H), 7.70-7.80 (m, 2H),8.31 (d, 1H), 8.46 (d, 2H), 8.55 (d, 1H), 10.59 (s, 1H); HPLC Purity:99.21%; LCMS: 563 (M⁺+1).

N-(4-(4-(2-hydroxy-3,4-dimethoxy-6-methylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-126)

¹H NMR (400 MHz, DMSO-d6) δ: 2.11 (s, 3H), 3.18 (br s, 4H), 3.30 (br s,4H), 3.66 (s, 3H), 3.75 (s, 3H), 4.18 (s, 2H), 6.48 (s, 1H), 7.20 (dd,4H), 7.70-7.80 (m, 2H), 8.31 (d, 1H), 8.44 (d, 2H), 8.52 (d, 1H), 8.78(br s, 1H), 9.10 (br s, 1H), 9.19 (s, 1H), 9.60 (br s, 1H), 10.53 (s,1H); HPLC Purity: 97.01%; LCMS: 577 (M⁺+1).

N-(4-(4-(4-butoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-127)

¹H NMR (400 MHz, DMSO-d6) δ: 0.92 (t, 3H), 1.41 (sextet, 2H), 1.68(pentate, 2H), 3.00 (br s, 2H), 3.15 (br s, 2H), 3.25 (br s, 4H), 3.92(t, 2H), 4.22 (s, 2H), 6.97 (d, 2H), 7.20 (dd, 4H), 7.38 (d, 2H),7.70-7.79 (m, 2H), 8.44 (d, 1H), 8.50 (d, 1H), 9.12 (s, 1H), 9.64 (br s,1H), 10.50 (s, 1H); HPLC Purity: 98.86%; LCMS: 559 (M⁺+1).

N-(4-(4-(3-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-128)

¹H NMR (400 MHz, DMSO-d6) δ: 2.81 (br s, 2H), 3.00 (br s, 6H), 4.20 (brs, 2H), 6.80 (s, 2H), 7.20 (dd, 4H), 7.70-7.80 (m, 2H), 8.31 (d, 1H),8.46 (d, 2H), 8.55 (d, 1H), 9.17 (s, 1H), 9.70 (br s, 1H), 10.56 (s,1H); HPLC Purity: 99.28%; LCMS: 503 (M⁺+1).

4-((4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)methyl)phenylbutyrate (VIII-129)

¹H NMR (400 MHz, DMSO-d6) δ: 0.99 (t, 3H), 1.61 (sextet, 2H), 2.56 (t,2H), 3.03 (br s, 4H), 3.61 (br s, 4H), 4.24 (br s, 2H), 7.10-7.20 (m,5H), 7.45 (d, 2H), 7.65-7.72 (m, 2H), 8.23 (d, 1H), 8.41 (d, 2H), 8.51(d, 1H), 9.10 (s, 1H), 9.78 (br s, 1H), 10.50 (s, 1H); HPLC Purity:99.17%; LCMS: 573 (M⁺+1).

4-((4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)methyl)phenylacetate (VIII-130)

¹H NMR (400 MHz, DMSO-d6) δ 2.24 (s, 3H), 2.38 (br s, 4H), 3.42 (br s,4H), 3.78 (s, 2H), 7.10 (d, 2H), 7.20 (d, 2H), 7.44 (d, 2H), 7.63-7.71(m, 2H), 8.25 (d, 1H), 8.41 (d, 2H), 8.45 (d, 1H), 9.10 (s, 1H), 9.70(br s, 1H), 10.50 (s, 1H); HPLC Purity: 95.24%; LCMS: 545 (M⁺+1).

N-(4-(4-(3,4,5-trimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-131)

¹H NMR (400 MHz, DMSO-d6) δ: 3.75 (s, 3H), 3.81 (s, 6H), 4.22 (s, 2H),6.78 (s, 2H), 7.21 (q, 4H), 7.63-7.68 (m, 2H), 8.16 (d, 1H), 8.40 (d,2H), 9.10 (s, 1H); HPLC Purity: 98.81%; LCMS: 577 (M⁺+1).

N-(4-(4-(3-isobutoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-132)

¹H NMR (400 MHz, DMSO-d6) δ: 1.00 (d, 6H), 2.02 (septet, 1H), 3.05 (brs, 4H), 3.30 (br s, 4H), 3.80 (d, 2H), 3.91 (d, 2H), 7.00-7.08 (m, 2H),7.20 (dd, 4H), 7.39 (t, 1H), 7.71-7.80 (m, 2H), 8.30 (d, 1H), 8.45 (d,1H), 8.58 (d, 1H), 9.15 (s, 1H), 9.90 (br s, 1H), 10.58 (s, 1H); HPLCPpurity: 99.17%; LCMS: 559 (M⁺+1).

N-(4-(4-(2,3-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-133)

¹H NMR (400 MHz, DMSO-d6) δ: 2.25 (br s, 4H), 3.41 (br s, 4H), 3.64 (s,3H), 3.72 (s, 2H), 3.78 (s, 3H), 6.80-7.05 (m, 6H), 7.21 (q, 1H),7.59-7.70 (m, 2H), 8.14 (d, 1H), 8.38-8.42 (m, 2H), 9.01 (s, 1H); HPLCPurity: 98.50%; LCMS: 547 (M⁺+1).

N-(4-(4-(3-fluoro-4-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-134)

¹H NMR (400 MHz, DMSO-d6) δ: 2.81 (br s, 2H), 3.01 (br s, 2H), 3.25 (brs, 4H), 3.82 (s, 2H), 3.90 (s, 3H), 7.17 (d, 2H), 7.21 (d, 3H), 7.35(1H), 7.70-7.78 (m, 2H), 8.30 (d, 1H), 8.43 (d, 2H), 8.55 (d, 1H), 9.12(br s, 1H), 10.58 (s, 1H); HPLC Purity: 95.38%; LCMS: 535 (M⁺+1).

N-(4-(4-(3-fluoro-2-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-135)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.43 (br s, 4H), 3.62 (s,2H), 4.38 (s, 1H), 6.90 (q, 1H), 7.10-7.28 (m, 6H), 7.62 (d, 2H), 8.18(d, 1H), 8.40 (d, 2H), 9.10 (s, 1H); HPLC purity: 98.81%; LCMS: 521(M⁺+1).

N-(4-(4-(2,4-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-136)

¹H NMR (400 MHz, DMSO-d6) δ: 2.52 (br s, 4H), 3.30 (br s, 4H), 3.70-3.98(m, 8H), 6.58-6.64 (m, 2H), 7.16 (d, 2H), 7.22 (d, 2H), 7.33 (d, 1H),7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.44 (d, 2H), 8.55 (d, 1H), 9.10 (s,1H), 9.50 (br s, 1H), 10.51 (s, 1H); HPLC Purity: 92.62%; LCMS: 547(M⁺+1).

N-(4-(4-(3,4-dimethylbenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-137)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20 (s, 3H), 2.25 (br s, 4H), 2.50 (s,3H), 3.42 (br s, 4H), 3.81 (s, 2H), 6.96-7.20 (m, 7H), 7.68-7.76 (m,2H), 8.26 (d, 1H), 8.40 (d, 2H), 8.54 (d, 1H), 9.13 (s, 1H), 10.40 (brs, 1H); HPLC Purity: 96.74%; LCMS: 515 (M⁺+1).

N-(4-(4-(3-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-138)

¹H NMR (400 MHz, DMSO-d6) δ:1.70 (t, 2H), 2.24 (br s, 4H), 2.48-2.60 (m,4H), 3.44 (br s, 4H), 7.18-7.24 (m, 8H), 7.70-7.79 (m, 2H), 8.30 (d,1H), 8.42 (d, 1H), 8.58 (d, 1H), 9.16 (s, 1H), 10.41 (s, 1H); HPLCPurity: 93.22%; LCMS: 515 (M⁺+1).

3-((4-(4-(quinoline-8-sulfonamido)benzoyl)piperazin-1-yl)methyl)phenylacetate (VIII-139)

¹H NMR (400 MHz, DMSO-d6) δ: 2.24 (s, 4H), 2.30 (br s, 2H), 3.40 (br s,4H), 3.52 (s, 2H), 7.01-7.21 (m, 6H), 7.38 (t, 1H), 7.70-7.79 (m, 2H),8.29 (d, 1H), 8.42 (d, 1H), 8.58 (d, 1H), 9.15 (s, 1H), 10.41 (s, 1H);HPLC Purity: 93.39%; LCMS: 545 (M⁺+1).

N-(4-(4-(1-phenylethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-140)

¹H NMR (400 MHz, DMSO-d6) δ 1.22 (d, 3H), 2.20 (br s, 2H), 2.24 (br s,2H), 3.42 (br s, 4H), 3.68 (s, 2H), 7.04 (s, 3H), 7.17-7.26 (m, 4H),7.66-7.74 (m, 2H), 8.24 (d, 1H), 8.39 (d, 1H), 8.50 (d, 1H), 9.16 (s,1H), 10.40 (s, 1H); HPLC Purity: 99.27%; LCMS: 501 (M⁺+1).

N-(4-(4-((1-phenylcyclopropyl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-141)

¹H NMR (400 MHz, DMSO-d6) δ: 1.03 (d, 4H), 2.38 (br s, 2H), 2.61 (s,2H), 3.50 (br s, 4H), 7.19 (s, 4H), 7.25 (t, 1H), 7.36 (t, 2H), 7.42 (d,2H), 7.60-7.65 (m, 2H), 8.18 (d, 1H), 8.40 (d, 1H), 9.12 (s, 1H); HPLCPurity: 94.05%; LCMS: 527 (M⁺+1).

N-(4-(4-(2-hydroxy-3,4-dimethoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide (VIII-142)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (brs, 4H), 3.06 (br s, 4H), 3.65 (s,2H), 3.70 (s, 3H), 3.80 (s, 3H), 4.18 (s, 1H), 6.59 (d, 1H), 7.00 (d,1H), 7.18 (dd, 4H), 7.68-7.77 (m, 2H), 8.26 (d, 1H), 8.48 (d, 3H), 8.53(d, 1H), 9.18 (s, 1H), 9.42 (br s, 1H), 9.61 (s, 1H), 10.51 (s, 1H);HPLC Purity: 93.10%; LCMS: 563 (M⁺+1).

N-(4-(4-(2-fluoro-4-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-143)

¹H NMR (400 MHz, DMSO-d6) δ: 2.39 (br s, 4H), 3.20 (br s, 4H), 3.72 (s,2H), 3.80 (s, 3H), 6.79 (s, 1H), 6.90-7.01 (m, 2H), 7.18-7.24 (m, 2H),7.44 (br s, 1H), 7.71-7.80 (m, 2H), 8.30 (d, 1H), 8.49 (d, 1H), 8.57 (d,1H), 9.18 (s, 1H), 9.82 (br s, 1H), 10.48 (s, 1H); HPLC Purity: 96.28%;LCMS: 435 (M⁺+1).

N-(4-(4-(4-hydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-144)

¹H NMR (400 MHz, DMSO-d6) δ: 2.42 (br s, 4H), 3.20 (br s, 4H), 3.71 (s,2H), 6.77 (d, 1H), 6.84 (d, 2H), 7.18-7.24 (m, 5H), 7.61-7.67 (m, 2H),8.17 (d, 1H), 8.40 (d, 2H), 9.10 (s, 1H); HPLC Purity: 92.29%; LCMS: 503(M⁺+1).

N-(4-(4-(2,5-dihydroxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-145)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.38 (br s, 4H), 3.50 (s,2H), 6.45-6.59 (m, 3H), 7.04-7.18 (m, 4H), 7.65-7.77 (m, 2H), 8.24 (d,1H), 8.40 (d, 1H), 8.50 (d, 1H), 8.61 (s, 1H), 9.18 (s, 1H), 10.41 (s,1H); HPLC Purity: 98.19%; LCMS: 519 (M⁺+1).

N-(4-(4-(pyridin-3-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-146)

¹H NMR (400 MHz, DMSO-d6) δ: 2.25 (br s, 4H), 3.30 (br s, 4H), 3.59 (s,2H), 7.06-7.18 (s, 3H), 7.35-7.40 (m, 1H), 7.65-7.77 (m, 2H), 8.26 (d,1H), 8.40-8.56 (m, 3H), 9.18 (s, 1H), 10.41 (s, 1H); HPLC Purity:99.48%; LCMS: 488 (M⁺+1).

N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-147)

¹H NMR (400 MHz, DMSO-d6) δ:0.03 (s, 2H), 0.43 (s, 2H), 0.78-0.84 (m,1H), 2.18 (d, 2H), 2.39 (br s, 4H), 3.25 (br s, 2H), 3.46 (br s, 2H),7.10-7.19 (m, 3H), 7.76-7.80 (m, 2H), 8.26 (d, 1H), 8.43 (d, 1H), 8.58(d, 1H), 9.17 (s, 1H), 10.41 (s, 1H); HPLC Purity: 98.98%; LCMS: 451(M⁺+1).

N-(4-(4-((3-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-148)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.21 (br s, 2H), 3.46 (brs, 4H), 3.62 (s, 2H), 7.06-7.11 (m, 3H), 7.40 (t, 1H), 7.62-7.77 (m,2H), 8.21 (d, 1H), 8.25 (dd, 2H), 8.50 (d, 1H), 9.18 (s, 1H), 10.41 (s,1H); HPLC Purity: 98.83%; LCMS: 506 (M⁺+1).

N-(4-(4-((4-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-149)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.31 (br s, 4H), 3.62 (s,2H), 7.06-7.17 (m, 3H), 7.62-7.77 (m, 2H), 8.21 (d, 1H), 8.38 (d, 1H),8.50 (d, 1H), 8.72 (s, 1H), 8.90 (s, 1H), 9.10 (s, 1H), 10.40 (s, 1H);HPLC Purity: 99.86%; LCMS: 556 (M⁺+1).

N-(4-(4-((3-(trifluoromethyl)pyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-150)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.21 (br s, 2H), 3.46 (brs, 2H), 3.70 (s, 2H), 7.06-7.11 (m, 4H), 7.50 (t, 1H), 7.68-7.77 (m,2H), 8.15 (d, 1H), 8.25 (d, 1H), 8.40 (d, 1H), 8.50 (d, 1H), 8.76 (s,1H), 9.18 (s, 1H), 10.41 (s, 1H); HPLC Purity: 98.67%; LCMS: 556 (M⁺+1).

N-(4-(4-((5-chloropyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-151)

¹H NMR (400 MHz, DMSOd₆) δ: 2.31 (br s, 4H), δ 3.38 (br s, 4H), 3.72 (s,2H), 6.91-7.06 (m, 4H), 7.40 (d, 2H), 7.56-7.63 (m, 2H), 8.0-8.3 (m,4H), 9.18 (s, 1H); HPLC: 98.2%; LCMS: 523.2 (M⁺+1).

N-(4-(4-((4-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-152)

¹H NMR (400 MHz, DMSOd₆) δ: 2.38 (br s, 4H), 3.51 (br s, 4H), 3.61 (s,2H), 7.21-7.81 (m, 6H), 7.40 (m, 2H), 7.56-7.63 (m, 2H), 8.01 (m, 1H),8.56 (m, 1H), 9.18 (s, 1H); HPLC Purity: 98.2%; LCMS: 518.1 (M⁺+1).

N-(4-(4-((3-fluoropyridin-4-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-153)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (s, 4H), 3.31 (br s, 4H), 3.64 (m, 2H),7.0-7.6 (m, 6H), 7.40 (m, 2H), 7.0-7.6 (m, 2H), 8.56 (m, 2H), 9.18 (s,1H); HPLC Purity: 96.5% LCMS: 506.1 (M++1).

N-(4-(4-((5-fluoropyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-154)

¹H NMR (400 MHz, DMSOd₆) δ: 2.38 (s, 2H), 3.31 (m, 2H), 3.41 (m, 2H),3.64 (m, 2H), 7.0-7.6 (m, 6H), 7.40 (m, 2H), 7.0-7.6 (d, 2H), 8.56 (d,2H), 9.18 (m, 1H), 10.3 (m, 1H); HPLC Purity: 98.5%; LCMS: 506.1 (M⁺+1).

N-(4-(4-((5-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-155)

¹H NMR (400 MHz, DMSOd₆) δ: 2.38 (s, 4H), 3.32 (br s, 2H), 3.52 (br s,2H), 3.8 (s, 2H), 7.0-7.6 (m, 6H), 7.40 (m, 2H), 7.0-7.6 (d, 2H), 8.56(d, 2H), 9.18 (m, 1H); HPLC Purity: 99.3%; LCMS: 506.1 (M⁺+1).

N-(4-(4-((3-methoxypyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-156)

¹H NMR (400 MHz, DMSO-d₆) δ:2.38 (s, 4H), 3.41 (m, 4H), 3.8 (m, 2H),3.91 (s, 3H), 7.0-7.7 (m, 8H), 8.0-8.51 (m, 4H), 9.12 (m, 1H), 10.4 (s,1H); HPLC Purity: 97.3%; LCMS: 518.3 (M⁺+1).

N-(4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-157)

¹H NMR (400 MHz, DMSO-d₆) δ:2.41 (br s, 4H), 3.21 (m, 4H), 3.3-3.8 (m,2H), 7.05-7.71 (m, 8H), 8.22-8.62 (m, 5H), 9.12 (m, 1H), 10.4 (s, 1H);HPLC Purity: 99.3%; LCMS: 505.2 (M⁺+1).

N-(4-(4-((2-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-158)

¹H NMR (400 MHz, DMSO-d₆) δ: 2.41 (br s, 4H), 3.21 (s, 4H), 3.3-3.8 (brs, 2H), 7.05-7.72 (m, 10H), 8.22-8.61 (m, 3H), 9.12 (m, 1H), 10.41 (s,1H); HPLC Purity: 98.6%; LCMS: 505.2 (M⁺+1).

N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-159)

¹H NMR (400 MHz, DMSO-d₆) δ:0.04-0.45 (m, 2H), 0.61-0.66 (m, 2H),1.4-1.6 (m, 1H), 2.21-2.38 (m, 4H), 2.61 (d, 2H), 3.31-3.61 (br s, 4H),6.94-7.06 (m, 4H), 7.40 (d, 2H), 7.56-7.63 (m, 2H), 8.28 (d, 1H), 9.18(s, 1H), 10.4 (s, 1H); HPLC Purity: 99.6%; LCMS: 451.3 (M⁺+1).

N-(4-(4-(cyclohexylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-160)

¹H NMR (400 MHz, DMSO-d₆) δ:0.8 (m, 2H), 1.2 (m, 4H), 1.4 (s, 1H), 1.7(m, 4H), 2.32 (m, 4H), 2.62 (br s, 2H), 3.42 (br s, 4H), 7.0-7.4 (m,4H), 7.5-7.7 (m, 2H), 8.3-8.6 (m, 3H), 9.1 (d, 1H), 10.4 (s, 1H); HPLCPurity: 99.3%; MS: 493.3 (M⁺+1).

N-(4-(4-(4-chloro-3-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-161)

¹H NMR (400 MHz, DMSO-d₆) δ:2.22-2.41 (m, 4H), 3.21-3.81 (m, 6H),7.02-7.51 (m, 7H), 7.61-7.72 (m, 2H), 8.31-8.62 (m, 3H), 9.12 (d, 1H),10.4 (s, 1H); HPLC Purity: 96.8%; LCMS: 539.0 (M⁺+1).

N-(4-(4-(cyclopentylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-162)

¹H NMR (400 MHz, DMSO-d6) δ: 1.10 (sextet, 2H), 1.40-1.53 (m, 4H), 1.60(br s, 2H), 1.99 (pentate, 1H), 2.20 (d, 4H), 2.43 (br s, 2H), 3.32 (brs, 4H), 7.10 (t, 4H), 7.62-7.69 (m, 5H), 8.25 (d, 1H), 8.40 (d, 1H),8.47 (d, 1H), 9.10 (d, 1H), 10.28 (s, 1H); HPLC Purity: 98.26%; LCMS:479 (M⁺+1).

N-(4-(4-((tetrahydrofuran-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-163)

¹H NMR (400 MHz, DMSO-d6) δ 1.42 (sextet, 1H), 1.6-1.8 (m, 2H),2.20-2.40 (m, 4H), 3.42-3.52 (m, 4H), 3.61-3.75 (m, 4H), 3.80-4.05 (m,2H), 7.04-7.14 (m, 4H), 7.62-7.69 (m, 2H), 8.25 (d, 1H), 8.40 (d, 1H),8.47 (d, 1H), 9.10 (d, 1H); HPLC Purity: 98.26%; LCMS: 479 (M⁺+1).

N-(4-(4-((3-chloropyridin-4-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-164)

¹H NMR (400 MHz, DMSO-d6) δ 2.37 (br s, 4H), 3.42 (br s, 4H), 3.59 (s,2H), 7.10 (q, 4H), 7.50 (s, 1H), 7.62-7.69 (m, 2H), 8.25 (d, 1H), 8.42(d, 1H), 8.46-8.52 (m, 2H), 8.58 (s, 1H), 9.10 (d, 1H), 10.30 (s, 1H);HPLC Purity: 96.59%.; LCMS: 522 (M⁺).

N-(4-(4-((tetrahydrofuran-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-165)

¹H NMR (400 MHz, DMSO-d6) δ 1.62 (sextet, 1H), 1.72-1.92 (m, 2H),2.20-2.40 (m, 4H), 3.41-3.52 (m, 4H), 3.62-3.75 (m, 4H), 3.82-4.05 (m,2H), 7.04-7.14 (m, 4H), 7.62-7.69 (m, 2H), 8.25 (d, 1H), 8.40 (d, 1H),8.47 (d, 1H), 9.10 (d, 1H), 10.4 (s, 1H); HPLC Purity: 99.2%; LCMS: 479(M⁺+1).

N-(4-(4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-166)

¹H NMR (400 MHz, DMSO-d6) δ:2.37 (br s, 4H), 3.5-3.7 (m, 4H), 3.7-4.0(m, 2H), 7.1-7.3 (m, 6H), 7.50-7.62 (m, 4H), 8.0-8.3 (m, 2H), 9.10 (d,1H), 10.30 (s, 1H); HPLC Purity: 96.59%; LCMS: 522 (M⁺).

N-(4-(4-benzyl-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-167)

¹H NMR (400 MHz, DMSO-d6) δ:1.72 (dd, 2H), 2.41-2.72 (m, 2H), 3.22-3.42(m, 4H), 3.5-3.7 (m, 4H), 7.0-7.4 (m, 5H), 7.5-7.8 (m, 4H), 8.0-8.6 (m,3H), 9.1 (d, 1H), 10.4 (s, 1H); HPLC Purity: 98.59%; LCMS: 501.2 (M⁺+1).

N-(4-(4-(2-methoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-168)

¹H NMR (400 MHz, CDCl₃) δ: 2.06 (br s, 2H), 2.42 (br s, 4H), 3.62 (s,4H), 3.72 (br s, 3H), 3.80 (d, 2H), 6.82-6.97 (m, 2H), 7.06 (t, 2H),7.18 (t, 2H), 7.22-7.39 (m, 2H), 7.58-7.63 (m, 2H), 8.01 (d, 1H), 8.28(d, 1H), 8.38 (d, 1H), 8.56 (m, 2H), 9.18 (d, 1H); HPLC Purity: 98.10%;LCMS: 531 (M⁺+1).

N-(4-(4-(4-propoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-169)

¹H NMR (400 MHz, CD₃OD) δ: 1.04 (t, 3H), 1.80 (q, 2H), 2.06 (br s, 2H),3.55 (br s, 4H), 3.99 (t, 4H), 4.35 (s, 2H), 7.00-7.10 (m, 2H),7.19-7.28 (m, 3H), 7.66-7.70 (m, 2H), 8.19 (d, 1H), 8.42 (d, 2H), 9.18(d, 1H); HPLC Purity: 98.74%; LCMS: 559 (M⁺+1).

N-(4-(4-(2-propoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-170)

¹H NMR (400 MHz, CD₃OD) δ: 1.04 (t, 3H), 1.84 (br s, 2H), 2.16 (br s,2H), 3.58 (br s, 4H), 4.08 (br s, 2H), 4.25 (br d, 1H), 4.40 (s, 2H),7.04 (t, 1H), 7.19 (d, 1H), 7.20-7.28 (m, 4H), 7.44 (d, 1H), 7.53 (t,1H), 7.68-7.72 (m, 2H), 8.21 (d, 1H), 8.42 (d, 2H), 9.18 (d, 1H); HPLCPurity: 97.74%; LCMS: 559 (M⁺+1).

N-(4-(4-(2-isopropoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-171)

¹H NMR (400 MHz, CD₃OD) δ: 1.38 (s, 6H), 2.16 (br s, 2H), 3.55 (br s,3H), 4.18 (br d, 1H), 4.38 (s, 2H), 4.79 (s, 1H), 7.04 (t, 1H), 7.19 (d,1H), 7.21-7.34 (m, 4H), 7.40-7.52 (m, 2H), 7.53 (t, 1H), 7.67-7.72 (m,2H), 8.21 (d, 1H), 8.44 (d, 2H), 9.18 (s, 1H); LCMS: 559 (M⁺+1); HPLCPurity: 98.99%.

N-(4-(4-(3-isopropoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-172)

¹H NMR (400 MHz, CD₃OD) δ:1.38 (d, 6H), 1.4 (m, 1H), 2.08 (br s, 2H),3.18 (br s, 2H), 3.56 (br s, 4H), 4.38 (s, 2H), 4.68 (m, 2H), 6.99-7.10(m, 2H), 7.20-7.30 (m, 5H), 7.40 (t, 1H), 7.65-7.70 (m, 2H), 8.20 (d,1H), 8.43 (d, 2H), 9.18 (d, 1H); HPLC Purity: 99.68%; LCMS: 559 (M-+1).

N-(4-(4-(3-butoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-173)

¹H NMR (400 MHz, CD₃OD) δ: 1.01 (t, 3H), 1.50 (sextet, 2H), 1.79(pentate, 2H), 2.06 (br s, 2H), 3.58 (br s, 4H), 3.6-3.9 (m, 4H), 4.03(t, 2H), 4.38 (s, 2H), 7.00-7.08 (m, 3H), 7.19-7.26 (m, 4H), 7.41 (t,1H), 7.63-7.69 (m, 2H), 8.19 (d, 1H), 8.42 (d, 2H), 9.18 (d, 1H); HPLCPurity: 99.75%; LCMS: 573 (M-+1).

N-(4-(4-(2-hydroxy-3,4-dimethoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-174)

¹H NMR (400 MHz, CD₃OD) δ: 2.18 (br s, 2H), 3.18 (br s, 2H), 3.56 (br s,4H), 3.80 (s, 3H), 3.84 (s, 3H), 4.18 (br s, 2H), 4.30 (s, 2H), 6.61 (d,2H), 7.03 (d, 2H), 7.19-7.27 (m, 2H), 7.61-7.66 (m, 2H), 8.19 (d, 1H),8.42 (d, 2H), 9.18 (d, 1H); HPLC Purity: 97.61%; LCMS: 577 (M⁺+1).

N-(4-(4-(2-isopropylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-175)

¹H NMR (400 MHz, CD₃OD) δ: 1.22 (d, 6H), 2.05 (br s, 1H), 3.56 (br s,8H), 4.50 (s, 4H), 7.20-7.39 (m, 5H), 7.40-7.56 (m, 3H), 7.64-7.69 (m,2H), 8.20 (d, 1H), 8.42 (d, 2H), 9.18 (d, 1H); HPLC Purity: 98.73%;LCMS: 543 (M⁺+1).

N-(4-(4-(4-isobutoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-176)

¹H NMR (400 MHz, CD₃OD) δ: 1.04 (d, 6H), 2.02-2.17 (m, 3H), 3.15 (br d,2H), 3.56 (br d, 4H), 3.79 (d, 2H), 4.20 (br d, 2H), 4.35 (s, 2H), 7.02(d, 2H), 7.24 (t, 3H), 7.41 (d, 2H), 7.68-7.74 (m, 2H), 8.21 (d, 2H),8.42 (d, 2H), 9.18 (d, 1H); HPLC Purity: 98.56%; LCMS: 573 (M⁺+1).

N-(4-(4-(2-hydroxy-3-methoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-177)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.60 (brs, 4H), 2.70 (br s, 2H), 3.58 (br s, 2H), 3.78 (s, 2H), 3.9 (s, 3H),6.63 (d, 3H), 6.80 (br s, 1H), 7.12 (d, 2H), 7.77 (br s. 2H), 8.28 (s,1H), 8.42 (d, 2H), 8.58 (s, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLCPurity: 98.72%; LCMS: 547 (M⁺+1).

N-(4-(4-(2-(tert-butylthio)benzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-178)

¹H NMR (400 MHz, DMSO-d6) δ:1.20 (d, 9H), 1.61 (br s, 1H), 1.77 (br s,1H), 2.60 (br s, 1H), 2.70 (br s, 1H), 3.25 (br s, 2H), 3.58 (br s, 4H),3.83 (d, 2H), 7.10 (d, 3H), 7.20 (br s, 2H), 7.49 (br s, 1H), 7.77 (brs. 4H), 8.28 (s, 1H), 8.42 (d, 1H), 8.58 (s, 1H), 9.18 (s, 1H), 10.40(s, 1H); HPLC Purity: 91.52%; LCMS: 589 (M⁺+1).

N-(4-(4-(2-fluoro-6-methoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-179)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.60 (brs, 2H), 3.10 (br s, 2H), 3.45-3.55 (m, 4H), 3.64 (s, 3H), 3.81 (s, 2H),6.77-6.87 (m, 2H), 7.08-7.20 (m, 4H), 7.30 (br s, 1H), 7.77-7.80 (m.2H), 8.28 (d, 1H), 8.42 (d, 1H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s,1H); HPLC Purity: 99.88%; LCMS: 549 (M⁺+1).

N-(4-(4-(2-(methylthio)benzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-180)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.38 (d,4H), 2.60 (br s, 2H), 3.25 (br s, 2H), 3.58 (s, 2H), 3.6 (s, 3H),7.00-7.18 (m, 5H), 7.24 (d, 2H), 7.77-7.80 (d, 2H), 8.28 (d, 1H), 8.42(d, 2H), 8.58 (s, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.77%;LCMS: 547 (M⁺+1).

N-(4-(4-(5-chloro-2-hydroxy-4-methylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-181)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.25 (s,4H), 2.78 (br s, 2H), 3.50-3.78 (m, 4H), 6.78 (d, 1H), 7.10-7.20 (m,4H), 7.77-7.80 (m. 2H), 8.28 (s, 1H), 8.42 (d, 2H), 8.58 (s, 1H), 9.18(s, 1H), 10.40 (s, 1H); HPLC Purity: 99.85%; LCMS: 565 (M⁺+1).

N-(4-(4-(3-phenylpropyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-182)

¹H NMR (400 MHz, DMSO-d6) δ:1.32 (m, 2H), 1.61 (br s, 2H), 1.77 (br s,2H), 2.1 (t, 2H), 2.38 (d, 2H), 2.60 (br s, 1H), 3.28 (br s, 3H), 3.58(br s, 2H), 7.05-7.31 (m, 7H), 7.77-7.80 (m, 3H), 8.28 (d, 1H), 8.42 (d,2H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.73%;LCMS: 529 (M⁺+1).

N-(4-(4-(3-chloro-4-methoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-183)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.60 (brs, 2H), 3.22 (br s, 2H), 3.57 (s, 4H), 3.82 (s, 2H), 7.01-7.38 (m, 6H),7.77 (br s. 2H), 8.28 (s, 1H), 8.42 (d, 1H), 8.58 (s, 1H), 9.18 (s, 1H),10.40 (s, 1H); HPLC Purity: 99.50%; LCMS: 565 (M⁺+1).3-((4-(4-(quinoline-8-sulfonamido)benzoyl)-1,4-diazepan-1-yl)methyl)phenylacetate (VIII-184):

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.60 (brs, 4H), 2.70 (br s, 2H), 3.58 (br s, 2H), 3.78 (s, 2H), 6.63 (d, 2H),6.80 (br s, 2H), 7.12 (d, 2H), 7.77 (br s. 2H), 8.28 (s, 1H), 8.42 (d,2H), 8.58 (s, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity: 98.72%;LCMS: 547 (M⁺+1).

N-(4-(4-(4-methylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-185)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.26 (s,3H), 2.39-2.62 (m, 4H), 3.10 (br s, 2H), 3.50 (br s, 4H), 7.01-7.20 (m,7H), 7.77-7.80 (m, 2H), 8.28 (br s, 1H), 8.42 (d, 1H), 8.58 (d, 2H),9.18 (s, 1H), 10.41 (s, 1H); HPLC Purity: 97.70%; LCMS: 515 (M⁺+1).

N-(4-(4-(2,4-dichlorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-186)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.50-2.76(m, 2H), 3.45-3.70 (m, 4H), 3.7-3.9 (m, 4H), 7.05-7.20 (m, 2H),7.36-7.60 (m, 4H), 7.77-7.80 (m, 2H), 8.28 (d, 1H), 8.42 (d, 1H), 8.58(d, 2H), 9.18 (s, 1H), 10.41 (s, 1H); HPLC Purity: 99.76%; LCMS: 569(M⁺+1).

N-(4-(4-(4-(trifluoromethyl)benzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-187)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.50-2.60(m, 2H), 3.10 (br s, 2H), 3.50 (br s, 4H), 3.55-3.9 (m, 2H), 7.10 (s,4H), 7.20-7.38 (m, 3H), 7.77-7.80 (m, 2H), 8.28 (br s, 1H), 8.42 (d,1H), 8.58 (d, 2H), 9.18 (s, 1H), 10.41 (s, 1H); MS: 569 (M⁺+1); HPLCPurity: 99.47%; LCMS: 569 (M⁺+1).

N-(4-(4-(2-phenylpropyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-188)

¹H NMR (400 MHz, CD₃OD) δ: 1.0 (q, 1H), 1.36 (d, 3H), 2.04 (br s, 2H),3.10 (br s, 2H), 3.44 (br s, 4H), 3.56 (br s, 2H), 4.09 (br s, 2H), 7.10(s, 4H), 7.24-7.40 (m, 4H), 7.62-7.68 (m, 3H), 8.18 (d, 1H), 8.42 (d,2H), 9.18 (s, 1H); HPLC Purity: 99.86%; LCMS: 529 (M⁺+1).

N-(4-(4-phenethyl-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-189)

¹H NMR (400 MHz, CD₃OD) δ: 2.10 (br s, 2H), 3.06 (br s, 2H), 3.40 (br s,4H), 3.62 (br s, 2H), 3.79 (t, 2H), 4.09 (br s, 2H), 7.20-7.39 (m, 8H),7.62-7.68 (m, 2H), 8.18 (d, 1H), 8.42 (d, 2H), 9.18 (s, 1H); HPLCPurity: 97.56%; LCMS: 515 (M⁺+1).

N-(4-(4-(4-butylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-190)

¹H NMR (400 MHz, CD₃OD) δ: 0.92 (t, 3H), 1.37 (sextet, 2H), 1.58(sextet, 2H), 2.03 (br s, 2H), 2.62 (t, 2H), 3.16 (br s, 2H), 3.50 (brs, 4H), 4.19 (br s, 2H), 4.24 (s, 2H), 7.17-7.23 (m, 4H), 7.25-7.38 (m,4H), 7.61-7.65 (m, 2H), 8.18 (d, 1H), 8.41 (d, 2H), 9.16 (s, 1H); HPLCPurity: 99.72%; LCMS: 557 (M⁺+1).

N-(4-(4-(3,5-dimethylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-191)

¹H NMR (400 MHz, CD₃OD) δ: 2.01 (br s, 2H), 2.28 (s, 6H), 3.10 (br s,2H), 3.44 (br s, 4H), 3.18 (br s, 1H), 4.12 (s, 2H), 7.02 (s, 2H), 7.10(s, 1H), 7.14-7.22 (m, 4H), 7.60-7.65 (m, 2H), 8.18 (d, 1H), 8.42 (d,2H), 9.18 (s, 1H); HPLC Purity: 99.81%; LCMS: 529 (M⁺+1).

N-(4-(4-(2-hydroxy-3,4-dimethoxy-6-methylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-192)

¹H NMR (400 MHz, CD₃OD) δ: 2.12 (br s, 2H), 2.38 (s, 3H), 3.58 (br s,5H), 3.79 (s, 3H), 3.83 (s, 3H), 3.85-3.9 (m, 2H), 4.21 (br s, 1H), 4.38(s, 2H), 6.50 (s, 1H), 7.20-7.30 (m, 4H), 7.62-7.68 (m, 2H), 8.18 (d,1H), 8.42 (d, 2H), 9.18 (s, 1H); HPLC Purity: 98.77%; LCMS: 591 (M⁺+1).

N-(4-(4-(3,5-dimethoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-193)

¹H NMR (400 MHz, CD₃OD) δ: 2.02 (br s, 2H), 3.51 (br s, 3H), 3.2-3.7 (m,3H), 3.79 (s, 2H), 3.81 (s, 6H), 4.28 (s, 2H), 6.63 (d, 2H), 7.20-7.27(m, 5H), 7.62-7.68 (m, 2H), 8.18 (d, 1H), 8.42 (d, 2H), 9.18 (s, 1H);HPLC Purity: 94.85%; LCMS: 561 (M⁺+1).

N-(4-(4-(4-chloro-2-fluorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-193)

¹H NMR (400 MHz, CD₃OD) δ 2.03 (br s, 2H), 3.40 (br s, 4H), 3.61 (br s,2H), 4.38 (s, 2H), 6.63 (d, 2H), 7.15-7.27 (m, 4H), 7.32-7.38 (m, 2H),7.52 (t, 1H), 7.60-7.65 (m, 2H), 8.18 (d, 1H), 8.41 (d, 2H), 9.18 (s,1H); HPLC Purity: 99.99%; LCMS: 553 (M⁺).

N-(4-(4-(4-ethoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-194)

¹H NMR (400 MHz, CD₃OD) δ: 1.39 (t, 3H), 2.03 (br s, 2H), 3.10 (br s,1H), 3.57 (br s, 5H), 3.71 (br s, 2H), 4.06 (q, 2H), 4.19 (br s, 1H),4.30 (s, 1H), 6.63 (d, 2H), 7.00 (d, 2H), 7.18-7.27 (m, 2H), 7.38 (d,2H), 7.62-7.68 (m, 2H), 8.18 (d, 1H), 8.42 (d, 2H), 9.18 (s, 1H); HPLCPurity: 98.87%; LCMS: 545.0 (M⁺+1).

N-(4-(4-(3-hydroxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-195)

¹H NMR (400 MHz, CD₃OD) δ: 2.02 (br s, 2H), 3.18 (br s, 2H), 3.59 (s,4H), 4.20 (br s, 2H), 4.31 (s, 2H), 6.90 (d, 3H), 7.19-7.32 (m, 5H),7.62-7.68 (m, 2H), 8.18 (d, 1H), 8.42 (d, 2H), 9.18 (s, 1H); HPLCPurity: 96.26%; LCMS: 517.2 (M⁺+1).

N-(4-(4-(2,3-dichlorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-196)

¹H NMR (400 MHz, CD₃OD) δ: 2.12 (br s, 2H), 3.53 (br s, 6H), 3.73 (br s,2H), 4.59 (s, 2H), 6.63 (d, 2H), 7.20-7.30 (m, 3H), 7.44 (t, 1H), 7.59(s, 1H), 7.63-7.68 (m, 2H), 7.78 (d, 1H), 8.18 (d, 1H), 8.42 (d, 1H),9.18 (s, 1H); HPLC Purity: 99.29%; LCMS: 569 (M+1).

N-(4-(4-(3,4-dichlorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-197)

¹H NMR (400 MHz, DMSOd₆) δ: 1.60 (br s, 1H), 1.78 (br s, 1H), 2.60 (brs, 2H), 2.62 (br s, 2H), 3.23 (br s, 2H), 3.58 (br s, 2H), 3.50-3.62 (m,2H), 7.07-7.18 (m, 3H), 7.24 (dd, 1H), 7.43-7.60 (m, 2H), 7.70-7.79 (m,2H), 8.24 (d, 1H), 8.42 (d, 2H), 8.55 (d, 1H), 9.18 (s, 1H), 10.42 (s,1H); HPLC Purity: 99.76%; LCMS: 569.1 (M⁺+1).

N-(4-(4-(3,5-difluorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-198)

¹H NMR (400 MHz, DMSOd₆) δ: 1.60 (br s, 1H), 1.78 (br s, 1H), 2.60 (brs, 2H), 2.62 (br s, 2H), 3.23 (br s, 4H), 3.50-3.62 (m, 2H), 6.95-7.20(m, 6H), 7.74 (s, 2H), 8.24 (d, 1H), 8.42 (d, 2H), 8.55 (d, 1H), 9.18(s, 1H), 10.42 (s, 1H); HPLC Purity: 98.49%; LCMS: 559.1 (M⁺+23).

N-(4-(4-(2,6-dimethoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-199)

¹H NMR (400 MHz, DMSO-d6) δ: 1.60 (br s, 1H), 1.71 (br s, 1H), 2.62 (brs, 3H), 3.21 (br s, 2H), 3.50 (s, 3H), 3.59 (s, 3H), 3.79 (s, 2H), 6.58(d, 1H), 6.61 (d, 2H), 7.02-7.21 (m, 4H), 7.62-7.68 (m, 2H), 8.18 (d,1H), 8.42 (d, 2H), 9.18 (s, 1H), 10.39 (s, 1H); HPLC Purity: 99.26%;LCMS: 561 (M⁺+1).

N-(4-(4-(3-chloro-4-fluorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-200)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.80 (br s, 1H), 3.42 (dd,6H), 7.08-7.18 (m, 3H), 7.20-7.55 (m, 3H), 7.70-7.80 (m, 2H), 8.28 (d,1H), 8.42 (d, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLCPurity: 99.54%; LCMS: 561 (M⁺).

N-(4-(4-(4-(1-amino-2-cyanopropyl)benzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-201)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.7 (s, 1H), 1.80 (br s,1H), 2.70 (t, 2H), 2.93 (s, 3H), 3.23 (br s, 2H), 3.40-3.59 (m, 4H),3.64 (t, 1H), 6.68 (t, 2H), 7.01-7.18 (m, 5H), 7.70 (br s, 2H), 8.28 (t,1H), 8.42 (d, 2H), 8.58 (t, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLCPurity: 96.64%; LCMS: 605 (M⁺+23).

N-(4-(4-(2-ethylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-202)

¹H NMR (400 MHz, DMSO-d6) δ: 1.0-1.17 (m, 2H), 1.2 (t, 3H), 1.59 (br s,1H), 1.74 (br s, 1H), 2.1 (m, 2H), 2.42-2.75 (m, 5H), 3.2-3.6 (m, 3H),7.01-7.22 (m, 7H), 7.75 (s, 2H), 8.28 (d, 1H), 8.42 (d, 2H), 8.58 (d,1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.16%; LCMS: 529 (M⁺+1).

N-(4-(4-(4-(hex-1-yn-1-yl)benzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-203)

¹H NMR (400 MHz, DMSO-d6) δ: 0.92 (t, 3H), 1.40-1.60 (m, 5H), 1.77 (brs, 2H), 3.20 (br s, 4H), 3.50 (br s, 6H), 7.03-7.38 (m, 7H), 7.78 (br s,2H), 8.28 (br s, 1H), 8.42 (d, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40(s, 1H); HPLC Purity: 99.77%; LCMS: 581 (M⁺+1).

N-(4-(4-(2-fluoro-6-hydroxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-204)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.60 (brs, 2H), 2.78 (br s, 1H), 3.20-3.42 (m, 3H), 3.58 (d, 2H), 3.79 (d, 2H),4.1 (s, 1H), 6.59 (br s, 2H), 7.10-7.20 (m, 4H), 7.71-7.80 (m. 2H), 8.28(d, 1H), 8.42 (d, 1H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLCPurity: 99.78%; LCMS: 535 (M⁺+1).

N-(4-(4-(2,4-dichloro-6-hydroxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-205)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.58-2.80(m, 3H), 3.20-3.68 (m, 5H), 3.79 (d, 2H), 6.78 (d, 1H), 6.99 (d, 1H),7.09-7.20 (m, 4H), 7.71-7.80 (m. 2H), 8.28 (d, 1H), 8.42 (d, 1H), 8.58(d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.58%. LCMS: 585(M⁺+1).

N-(4-(4-(2-hydroxy-6-methoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-206)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.60 (brs, 2H), 3.21 (br s, 2H), 3.42-3.58 (m, 2H), 3.53 (s, 2H), 3.68 (d, 2H),6.26-6.45 (m, 2H), 7.03-7.20 (m, 3H), 7.71-7.80 (m, 2H), 8.28 (s, 2H),8.42 (d, 2H), 8.58 (s, 1H), 9.18 (s, 1H), 10.41 (s, 1H); HPLC Purity:99.89%; LCMS: 547 (M⁺+1).

N-(4-(4-(4-cyanobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-207)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.60 (brs, 2H), 3.21 (br s, 2H), 3.42-3.58 (m, 2H), 3.53 (s, 2H), 3.68 (d, 2H),7.10-7.20 (m, 3H), 7.41-7.58 (m, 2H), 7.71-7.81 (m. 3H), 8.28 (d, 1H),8.42 (d, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity:97.75%; LCMS: 526.2 (M⁺+1).

N-(4-(4-(5-chloro-2-hydroxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-208)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.60-2.78(m, 2H), 3.21 (br s, 2H), 3.42-3.58 (m, 2H), 3.50-3.71 (m, 4H),6.74-6.80 (m, 1H), 7.08-7.20 (m, 5H), 7.71-7.80 (m. 2H), 8.28 (br s,1H), 8.42 (d, 2H), 8.58 (br s, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLCPurity: 99.40%; LCMS: 551.1 (M⁺).

N-(4-(4-(4-methoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-208)

¹H NMR (400 MHz, DMSO-d6) δ: 1.61 (br s, 1H), 1.77 (br s, 1H), 2.40 (brs, 1H), 2.60 (br s, 1H), 3.21 (br s, 2H), 3.42-3.58 (m, 4H), 3.77 (s,2H), 6.80-6.91 (m, 2H), 7.06-7.20 (m, 4H), 7.71-7.79 (m. 2H), 8.28 (brs, 1H), 8.42 (d, 2H), 8.58 (br s, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLCPurity: 99.04%; LCMS: 531 (M⁺+1).

N-(4-(4-(2,5-dimethylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-209)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.10-2.25(m, 2H), 2.24 (s, 2H), 2.60-2.67 (m, 2H), 2.60 (br s, 2H), 3.20-3.60 (m,2H), 6.90-7.20 (m, 5H), 7.71-7.80 (m. 2H), 8.28 (d, 1H), 8.42 (d, 2H),8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity: 98.86%; LCMS:529 (M⁺+1).

N-(4-(4-(3,5-dichlorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-210)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.24 (s,2H), 2.60-2.67 (m, 2H), 3.20-3.60 (br s, 2H), 3.8-3.9 (m, 4H), 7.09-7.20(m, 3H), 7.25-7.50 (m, 3H), 7.71-7.80 (m. 2H), 8.28 (d, 1H), 8.42 (d,1H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity: 99.29%;LCMS: 569 (M⁺−1).

N-(4-(4-(3-fluoro-4-(trifluoromethyl)benzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-211)

¹H NMR (400 MHz, DMSO-d6) δ:1.61 (br s, 1H), 1.77 (br s, 1H), 2.24 (s,2H), 2.40-2.60 (m, 2H), 3.20 (br s, 2H), 3.59 (br s, 2H), 3.58 (d, 2H),7.10-7.20 (m, 3H), 7.25-7.42 (m, 2H), 7.71-7.80 (m. 2H), 8.28 (d, 1H),8.42 (d, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity:99.71%; LCMS: 587 (M⁺+1).

N-(4-(4-(2,4,5-trimethylbenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-212)

¹H NMR (400 MHz, DMSO-d6) δ: 2.10 (s, 3H), 2.18 (s, 6H), 2.24 (s, 2H),2.40-2.60 (m, 4H), 3.20 (br s, 2H), 3.59 (br s, 2H), 3.58 (d, 2H),6.80-6.99 (m, 2H), 7.04-7.18 (m, 2H), 7.71-7.80 (m, 2H), 8.28 (d, 1H),8.42 (d, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 10.40 (s, 1H); HPLC Purity:99.80%; LCMS: 543 (M⁺+1).

N-(4-(4-(4-chlorobenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-213)

¹H NMR (400 MHz, DMSO-d6) δ:1.59 (s, 1H), 1.78 (s, 1H), 2.41 (s, 1H),2.52-2.64 (m, 2H), 3.25 (br s, 2H), 3.55 (s, 2H), 3.59 (s, 2H),7.08-7.17 (m, 3H), 7.20-7.40 (m, 4H), 7.68-7.75 (m, 2H), 8.28 (d, 1H),8.42 (d, 1H), 8.53 (d, 1H), 9.18 (s, 1H), 10.39 (s, 1H); HPLC Purity:97.45%; LCMS: 535.1 (M⁺).

N-(4-(4-(2,5-dimethoxybenzyl)-1,4-diazepane-1-carbonyl)phenyl)quinoline-8-sulfonamide(VIII-214)

¹H NMR (400 MHz, DMSO-d6) δ: 1.63 (br s, 1H), 1.78 (br s, 1H), 2.2 (brs, 2H), 2.62 (br s, 2H), 3.24 (br s, 2H), 3.48-3.66 (m, 4H), 3.7-3.86(s, 6H), 6.71-6.81 (m, 1H), 6.82-6.99 (m, 2H), 7.05-7.17 (m, 3H),7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.42 (d, 1H), 8.56 (d, 1H), 9.18 (s,1H), 10.39 (s, 1H); HPLC Purity: 98.43%; LCMS: 561 (M⁺+1).

Synthesis of Corresponding Salts:

General Procedure for making salts:

To a solution ofN-(4-(4-benzylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide (0.25mmol) in methanol (5 ml) added Sodium hydroxide/methanesulfonic acid(0.25 mmol, 1.0 eq) and the reaction mixture was stirred for 3 h at roomtemperature. The solvent was removed under reduced pressure andazeotroped with pentane to get the salts as pale yellow solid.

Sodium(4-(4-benzylpiperazine-1-carbonyl)phenyl)(quinolin-8-ylsulfonyl)amide(VIII-215)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.31 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 6.94 (d, 2H), 7.06 (t, 4H), 7.40 (d, 2H),7.56-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s,1H), 9.18 (s, 1H); LCMS: 508.5 (M⁺+23).

8-(N-(4-(4-benzylpiperazine-1-carbonyl)phenyl)sulfamoyl)quinolin-1-iummethanesulfonate (VIII-216)

¹H NMR (400 MHz, CDCl₃) δ: 2.38 (br d, 4H), 3.31 (br s, 2H), 3.41 (s,2H), 3.64 (br s, 2H), 6.94 (d, 2H), 7.06 (t, 4H), 7.40 (d, 2H),7.56-7.63 (m, 2H), 8.01 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 8.56 (s,1H), 9.18 (s, 1H); LCMS: 487.0 (M⁺+1).

Synthesis of Piperazine Based Benzyl Derivatives with 3-methyl,2-methyl, 3-fluoro, 3-chloro, 3-methoxy and 2-methoxy Substituted PhenylRings

The synthesis of compounds 140-145 and compound of formula (XIV) wascarried out starting from aniline 140 (0.25 mmol) by following thesimilar procedure as mentioned in Scheme 21 for compounds of formula(VIII) with respective key steps such as sulfonamide formation, esterhydrolysis, amide bond formation and reductive amination.

N-(4-(4-benzylpiperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-1)

¹H NMR (400 MHz, CDCl₃) δ: 2.22 (s, 3H), 2.65 (br s, 4H), 3.50 (br s,4H), 4.20 (s, 2H), 7.01 (d, 1H), 7.12 (s, 1H), 7.39 (t, 2H), 7.48 (q,2H), 7.60-7.68 (m, 2H), 8.18 (d, 1H), 8.28 (d, 1H), 8.43 (d, 1H), 9.18(d, 1H); HPLC Purity: 98.75%; LCMS: 501 (M-+1).

N-(4-(4-benzylpiperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-2)

¹H NMR (400 MHz, CDCl₃) δ: 2.62 (br s, 4H), 3.80 (br s, 4H), 4.20 (s,2H), 6.99 (d, 1H), 7.03 (d, 1H), 7.39 (d, 2H), 7.40-7.48 (m, 3H),7.60-7.68 (m, 2H), 7.80 (t, 1H), 8.18 (d, 1H), 8.26 (d, 1H), 8.43 (d,1H), 9.18 (d, 1H); HPLC Purity: 97.86%; LCMS: 505 (M⁺+1).

N-(4-(4-benzylpiperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-3)

¹H NMR (400 MHz, CDCl₃) δ: 2.46 (br s, 4H), 3.50 (br s, 4H), 3.66 (s,3H), 4.20 (br s, 2H), 6.40 (br s, 1H), 6.94 (br s, 1H), 7.39 (d, 2H),7.42-7.48 (m, 3H), 7.61-7.66 (m, 2H), 8.18 (d, 1H), 8.36 (d, 1H), 8.41(d, 1H), 9.18 (d, 1H); HPLC Purity: 99.99%; LCMS: 517 (M⁺+1).

N-(4-(4-benzylpiperazine-1-carbonyl)-3-chlorophenyl)quinoline-8-sulfonamide(XIV-4)

¹H NMR (400 MHz, CDCl₃) δ: 2.32 (br s, 4H), 3.42 (br s, 4H), 4.38 (s,2H), 7.16 (q, 2H), 7.30 (s, 1H), 7.49 (s, 4H), 7.64-7.73 (m, 2H), 8.21(d, 1H), 8.42 (t, 2H), 9.18 (d, 1H); HPLC Purity: 96.62% LCMS: 521 (M⁺).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-5)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.41 (br s,4H), 3.50 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.39 (dd, 2H), 7.54 (s,1H), 7.62-7.77 (m, 2H), 8.21-8.30 (m, 3H), 8.52 (d, 1H), 9.18 (s, 1H),9.34 (s, 1H); HPLC Purity: 97.97%; LCMS: 535 (M⁺).

N-(4-(4-(2,4-dichlorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-6)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.42 (br s,4H), 3.50 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.39 (dd, 2H), 7.54 (s,1H), 7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.52 (d, 1H), 9.18 (s, 1H);HPLC Purity: 97.97%; LCMS: 569 (M⁺).

N-(2-methyl-4-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-7)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.41 (br s,4H), 3.53 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.46 (d, 2H), 7.62-7.77(m, 4H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.21 (br s, 1H);HPLC Purity: 96.00%; LCMS: 569 (M⁺+1).

N-(4-(4-(3,5-dichlorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-8)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.46 (s,4H), 6.97 (s, 2H), 7.06 (s, 1H), 7.31 (s, 2H), 7.46 (s, 1H), 7.62-7.77(m, 3H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.39 (s, 1H);HPLC Purity: 99.45%; LCMS: 569 (M⁺)N-(4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-9):

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.30 (br s, 4H), 3.41 (br s,4H), 3.47 (s, 2H), 6.97 (s, 2H), 6.99-7.16 (m, 4H), 7.25-7.34 (m, 1H)7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.21(s, 1H); HPLC Purity: 97.71%; LCMS: 519 (M⁺+1).

N-(4-(4-(3,4-dichlorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-10)

¹H NMR (400 MHz, DMSO-d6) δ 2.01 (s, 3H), 2.25 (br s, 4H), 3.45 (s, 4H),6.97 (s, 2H), 7.06 (m, 1H), 7.25 (d, 1H) 7.58 (t, 2H), 7.62-7.77 (m,2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.21 (s, 1H); HPLCPurity: 94.90%; LCMS: 569 (M⁺).

N-(4-(4-(3,5-difluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-11)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.25 (br s, 4H), 3.45 (s,4H), 3.52 (s, 2H), 6.97-7.10 (m, 5H), 7.62-7.77 (m, 3H), 8.21-8.30 (m,2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.21 (s, 1H); HPLC Purity: 97.84%;LCMS: 536 (M⁺+23).

N-(4-(4-(3-chloro-4-fluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-12)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.25 (br s, 4H), 3.43 (s,4H), 3.46 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.21-7.35 (m, 2H), 7.42(d, 1H), 7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.53 (d, 1H), 9.18 (s,1H), 9.21 (s, 1H); HPLC Purity: 94.61%; LCMS: 553 (M⁺).

N-(4-(4-(4-chloro-2-fluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-13)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.25 (br s, 4H), 3.20 (br s,2H), 3.45 (s, 4H), 6.97 (s, 2H), 7.06 (s, 1H), 7.21 (d, 1H), 7.31-7.39(m, 2H), 7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s,1H), 9.21 (s, 1H); HPLC Purity: 96.23%; LCMS: 553 (M⁺).

N-(4-(4-(2,4-difluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-14)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.25 (br s, 4H), 3.20 (br s,2H), 3.45 (s, 4H), 6.97-7.06 (m, 4H), 7.20 (t, 1H), 7.31-7.39 (m, 1H),7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.21(s, 1H); HPLC Purity: 99.12%; LCMS: 537 (M⁺+1).

N-(4-(4-(2,3-dichlorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-15)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.25 (br s, 4H), 3.37 (s,4H), 3.45 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.25 (t, 1H) 7.42 (d,1H), 7.50 (d, 1H), 7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H),9.18 (s, 1H), 9.21 (s, 1H); HPLC Purity: 98.43%; LCMS: 569 (M⁺).

N-(4-(4-(2-fluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-16)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.30 (br s, 4H), 3.25 (s,4H), 3.47 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.10-7.20 (m, 2H),7.24-7.38 (m, 2H) 7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H),9.18 (s, 1H), 9.21 (s, 1H); HPLC Purity: 98.71%; LCMS: 519 (M⁺+1).

N-(4-(4-(3-chlorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-17)

¹H NMR (400 MHz, DMSO-d6) δ 2.01 (s, 3H), 2.37 (br s, 4H), 3.37 (br s,4H), 3.44 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.20-7.29 (m, 4H),7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.56 (d, 1H), 9.18 (s, 1H), 9.34(s, 1H); HPLC Purity: 99.25%; LCMS: 535 (M⁺).

N-(4-(4-(2,3-difluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-18)

¹H NMR (400 MHz, DMSO-d6) δ 2.01 (s, 3H), 2.25 (br s, 4H), 3.46 (br s,4H), 3.59 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.25-7.36 (m, 2H),7.63-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.21(s, 1H); HPLC Purity: 96.79%; LCMS: 537 (M⁺+1).

N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-19)

¹H NMR (400 MHz, DMSO-d6) δ:0.03-0.05 (m, 2H), 0.30-0.31 (m, 2H),0.45-0.47 (m, 1H), 2.01 (s, 3H), 2.17 (d, 2H), 2.25 (br s, 4H), 3.22 (brs, 4H), 3.59 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.63-7.77 (m, 2H),8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.21 (s, 1H); HPLCPurity: 98.31%; LCMS: 465 (M⁺+1).

N-(2-methyl-4-(4-(pyridin-4-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-20)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.25 (br s, 4H), 3.46 (br s,4H), 3.50 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.31 (m, 2H), 7.63-7.77(m, 3H), 8.21-8.30 (m, 2H), 8.54 (d, 1H), 8.58 (d, 1H), 9.18 (s, 1H),9.21 (br s, 1H); HPLC Purity: 94.88%; LCMS: 502 (M⁺+1).

N-(4-(4-(3,5-difluorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-21)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.52 (br s, 4H), 3.58 (s,2H), 7.01-7.18 (m, 4H), 7.38 (t, 1H), 7.71-7.82 (m, 3H), 8.32 (t, 2H),8.60 (d, 1H), 9.12 (s, 1H), 9.98 (s, 1H); HPLC Purity: 98.93%; LCMS: 541(M⁺+1).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-22)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.28 (br s, 4H), 3.55 (brs, 2H), 7.08 (t, 2H), 7.35-7.40 (m, 4H), 7.71-7.80 (m, 3H), 8.32 (t,2H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H); HPLC Purity: 98.58%;LCMS: 539 (M⁺).

N-(4-(4-(2,4-dichlorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-23)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 3H), 3.46 (br s, 4H), 3.58 (s,2H), 7.08 (t, 2H), 7.35 (t, 1H), 7.40 (d, 1H), 7.50 (d, 1H), 7.60 (s,1H), 7.71-7.79 (m, 2H), 8.32 (t, 2H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98(s, 1H); HPLC Purity: 98.58%; LCMS: 573 (M⁺).

N-(4-(4-(3,5-dichlorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-24)

¹H NMR (400 MHz, DMSO-d6) δ: 2.38 (br s, 4H), 3.28 (br s, 4H), 3.55 (brs, 2H), 7.10 (t, 2H), 7.30-7.38 (m, 3H), 7.50 (s, 1H), 7.71-7.80 (m,2H), 8.32 (t, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H); HPLCPurity: 97.63%; LCMS: 573 (M⁺).

N-(4-(4-(3-chloro-4-fluorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-25)

¹H NMR (400 MHz, DMSO-d6) δ: 2.38 (br s, 3H), 3.28 (br s, 4H), 3.55 (s,2H), 7.10 (t, 2H), 7.29-7.40 (m, 3H), 7.50 (d, 1H), 7.71-7.80 (m, 2H),8.30 (t, 2H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H); HPLC Purity:96.66%; LCMS: 557 (M⁺).

N-(2-fluoro-4-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-26)

¹H NMR (400 MHz, DMSO-d6) δ: 2.38 (br s, 4H), 3.46 (br s, 4H), 3.60 (s,2H), 7.10 (t, 2H), 7.35 (t, 1H), 7.59 (d, 2H), 7.63-7.78 (m, 4H), 8.32(t, 2H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H); HPLC Purity: 99.96%;LCMS: 573 (M⁺+1).

N-(4-(4-(3,4-dichlorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-27)

¹H NMR (400 MHz, DMSO-d6) δ: 2.38 (br s, 3H), 3.28 (br s, 4H), 3.55 (s,2H), 7.10 (t, 2H), 7.28-7.40 (m, 2H), 7.58 (t, 2H), 7.70-7.79 (m, 2H),8.32 (t, 2H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H); HPLC Purity:98.23%; LCMS: 573 (M⁺).

N-(2-fluoro-4-(4-(2-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-28)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.48 (br s, 4H), 3.58 (s,2H), 7.05-7.20 (m, 3H), 7.28-7.40 (m, 2H), 7.70-7.79 (m, 2H), 8.32 (t,2H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H); HPLC Purity: 96.54%;LCMS: 523 (M⁺+1).

N-(4-(4-(2,4-difluorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-29)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.22 (br s, 4H), 3.58 (s,2H), 7.03-7.20 (m, 3H), 7.20 (t, 1H), 7.38 (t, 1H), 7.44 (q, 1H),7.70-7.79 (m, 2H), 8.32 (t, 2H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s,1H); HPLC Purity: 99.52%; LCMS: 541 (M⁺+1).

N-(4-(4-(2,3-dichlorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-30)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.22 (br s, 4H), 3.58 (s,2H), 7.12 (m, 3H), 7.31-7.40 (m, 1H), 7.44 (d, 1H), 7.60 (d, 1H),7.70-7.79 (m, 2H), 8.32 (t, 2H), 8.60 (d, 1H), 9.12 (s, 1H), 9.98 (s,1H); HPLC Purity: 97.43%; LCMS: 573 (M⁺).

N-(4-(4-(4-chloro-2-fluorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-31)

¹H NMR (400 MHz, DMSO-d6) δ: 2.38 (br s, 3H), 3.22 (br s, 4H), 3.58 (s,2H), 7.10 (t, 2H), 7.23-7.46 (m, 4H), 7.70-7.79 (m, 2H), 8.32 (t, 2H),8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H); HPLC Purity: 99.89%; LCMS: 557(M⁺).

N-(4-(4-(2,3-difluorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-32)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 3H), 3.26 (br s, 4H), 3.58 (s,2H), 7.03-7.25 (m, 4H), 7.38 (t, 2H), 7.70-7.79 (m, 2H), 8.32 (t, 2H),8.60 (d, 1H), 9.12 (s, 1H), 9.98 (s, 1H); HPLC Purity: 99.04%; LCMS: 541(M⁺+1).

N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-33)

¹H NMR (400 MHz, DMSO-d6) δ:0.03-0.035 (m, 2H), 0.64-0.66 (m, 2H),0.81-0.83 (m, 1H), 2.20 (s, 2H), 2.38 (br s, 4H), 3.52 (br s, 4H), 7.10(m, 2H), 7.38 (t, 1H), 7.70-7.79 (m, 2H), 8.32 (t, 2H), 8.60 (d, 1H),9.12 (s, 1H), 9.98 (s, 1H); HPLC Purity: 97.67%; LCMS: 469 (M⁺+1).

N-(2-fluoro-4-(4-(pyridin-4-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-34)

¹H NMR (400 MHz, DMSO-d6) δ:2.38 (br s, 4H), 3.48 (br s, 4H), 3.59 (s,2H), 7.12 (t, 2H), 7.38 (s, 3H), 7.70-7.79 (m, 2H), 8.32 (t, 2H), 8.57(d, 2H), 8.60 (d, 1H), 9.10 (s, 1H), 9.98 (s, 1H); HPLC Purity: 97.70%;LCMS: 506 (M⁺+1).

N-(2-fluoro-4-(4-(pyridin-2-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-35)

¹H NMR (400 MHz, DMSO-d6) δ: 2.38 (br s, 4H), 3.22 (br s, 4H), 3.62 (s,2H), 7.13 (t, 2H), 7.22-7.38 (m, 2H), 7.42 (d, 1H), 7.70-7.79 (m, 3H),8.32 (t, 2H), 8.50 (s, 1H), 8.60 (d, 1H), 9.18 (s, 1H), 9.98 (s, 1H);HPLC Purity: 99.74%; LCMS: 506 (M⁺+1).

N-(2-methyl-4-(4-(pyridin-2-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-36)

¹H NMR (400 MHz, DMSO-d6) δ:2.01 (s, 3H), 2.38 (br s, 4H), 3.52 (br s,4H), 3.60 (s, 2H), 6.97 (s, 2H), 7.03 (s, 1H), 7.23 (t, 1H), 7.40 (d,1H), 7.64-7.78 (m, 4H), 8.25 (dd, 2H), 8.46 (d, 1H), 8.58 (d, 1H), 9.08(s, 1H); HPLC Purity: 98.36%; LCMS: 502 (M⁺+1).

N-(2-methyl-4-(4-(1-phenylethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-37)

¹H NMR (400 MHz, DMSO-d6) δ:1.21 (d, 3H), 2.01 (s, 3H), 2.18-2.40 (m,4H), 3.42 (br s, 4H), 3.46 (q, 1H), 6.90 (s, 2H), 7.01 (s, 1H),7.18-7.34 (m, 5H), 7.64-7.78 (m, 2H), 8.25 (dd, 2H), 8.38 (d, 1H), 9.18(s, 1H), 9.31 (s, 1H); HPLC Purity: 99.85%; LCMS: 515 (M⁺+1).

N-(2-methyl-4-(4-(2-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-38)

¹H NMR (400 MHz, DMSO-d6) δ:1.15 (d, 3H), 2.01 (s, 3H), 2.20-2.38 (m,6H), 3.48 (br s, 4H), 3.85 (q, 1H), 6.97 (s, 2H), 7.01 (s, 1H),7.05-7.30 (m, 5H), 7.62-7.76 (m, 2H), 8.25 (dd, 2H), 8.58 (d, 1H), 9.18(s, 1H), 9.31 (br s, 1H); HPLC Purity: 95.95%; LCMS: 529 (M⁺+1).

N-(2-methyl-4-(4-(3-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-39)

¹H NMR (400 MHz, DMSO-d6) δ:1.62 (m, 2H), 2.01 (s, 3H), 2.18-2.40 (m,6H), 2.56 (br s, 2H), 3.43-3.56 (m, 4H), 6.97 (s, 2H), 7.01 (s, 1H),7.13-7.28 (m, 5H), 7.64-7.78 (m, 2H), 8.25 (dd, 2H), 8.56 (d, 1H), 9.10(s, 1H), 9.31 (s, 1H); HPLC Purity: 98.98%; LCMS: 529 (M⁺+1).

N-(2-methyl-4-(4-phenethylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-40)

¹H NMR (400 MHz, CDCl₃) δ 2.01 (s, 3H), 2.38 (br s, 4H), 2.58 (t, 2H),2.65 (t, 2H), 3.50 (br s, 4H), 6.97 (s, 2H), 7.01 (s, 1H), 7.15-7.28 (m,5H), 7.62-7.78 (m, 2H), 8.25 (dd, 2H), 8.38 (d, 1H), 9.18 (s, 1H), 9.31(br s, 1H); LCMS: 515 (M-+1); HPLC Purity: 97.07%.

N-(3-methoxy-4-(4-phenethylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-41)

¹H NMR (400 MHz, DMSO-d6) δ 2.21-2.58 (m, 6H), 2.73-2.79 (m, 2H), 3.18(d, 2H), 3.66 (s, 3H), 6.38 (d, 1H), 6.87 (d, 2H), 7.19-7.30 (m, 4H),7.59-7.62 (m, 2H), 8.02 (d, 1H), 8.25 (d, 2H), 8.35 (d, 1H), 8.42 (s,2H), 9.18 (d, 1H); HPLC Purity: 99.42%; LCMS: 531 (M-+1).

N-(3-methoxy-4-(4-(1-phenylethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-42)

¹H NMR (400 MHz, CDCl₃) δ:1.34 (d, 3H), 2.15-2.40 (m, 4H), 3.20 (br s,4H), 3.35 (q, 1H), 3.62 (s, 3H), 6.35 (d, 1H), 6.82 (d, 2H), 7.18-7.28(m, 3H), 7.58-7.62 (m, 2H), 8.02 (d, 1H), 8.28 (d, 1H), 8.35 (d, 1H),8.41 (s, 1H), 9.18 (d, 1H); HPLC Purity: 97.00%; LCMS: 531 (M⁺+1).

N-(3-methoxy-4-(4-(2-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-43)

¹H NMR (400 MHz, CDCl₃) δ:1.21 (d, 3H), 2.12-2.45 (m, 6H), 2.84-2.93 (m,1H), 3.10 (br s, 4H), 3.62 (s, 3H), 6.37 (d, 1H), 6.82 (d, 2H), 7.18 (d,2H), 7.28 (d, 2H), 7.58-7.62 (m, 2H), 8.02 (d, 1H), 8.28 (d, 1H), 8.35(d, 1H), 8.41 (s, 1H), 9.18 (d, 1H); HPLC Purity: 99.00%; LCMS: 545(M⁺+1).

N-(3-methoxy-4-(4-(3-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-44)

¹H NMR (400 MHz, CDCl₃) δ: 1.78 (pentate, 2H), 2.20 (br s, 2H), 2.35 (t,4H), 2.60 (t, 2H), 3.15 (m, 4H), 3.62 (s, 3H), 6.35 (d, 1H), 6.84 (d,2H), 7.10-7.28 (m, 4H), 7.58-7.62 (m, 2H), 8.02 (d, 1H), 8.28 (d, 1H),8.35 (d, 1H), 8.41 (s, 1H), 9.18 (d, 1H); HPLC Purity: 99.00%; LCMS: 545(M⁺+1).

N-(2-fluoro-4-(4-phenethylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-45)

¹H NMR (400 MHz, CDCl₃) δ: 2.44 (m, 4H), 2.59 (br s, 2H), 2.76 (d, 2H),3.40 (br s, 2H), 3.62 (br s, 2H), 6.90 (d, 1H), 7.01 (d, 1H), 7.12-7.30(m, 4H), 7.58-7.62 (m, 2H), 7.70 (t, 1H), 8.02 (d, 1H), 8.28 (d, 1H),8.37 (d, 1H), 8.81 (br s, 1H), 9.18 (d, 1H); HPLC Purity: 96.00%; LCMS:519 (M⁺+1).

N-(2-fluoro-4-(4-(1-phenylethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-46)

¹H NMR (400 MHz, CDCl₃) δ:1.31 (d, 3H), 2.38 (br s, 4H), 3.36 (q, 3H),3.58 (br s, 2H), 6.82 (d, 1H), 7.00 (d, 1H), 7.18-7.30 (d, 5H),7.58-7.62 (m, 2H), 7.70 (t, 1H), 8.02 (d, 1H), 8.28 (d, 1H), 8.35 (d,1H), 8.41 (s, 1H), 8.80 (br s, 1H), 9.18 (d, 1H); HPLC Purity: 99.00%;LCMS: 519 (M++).

N-(2-fluoro-4-(4-(2-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-47)

¹H NMR (400 MHz, CDCl₃) δ:1.21 (d, 3H), 2.20-2.55 (m, 6H), 2.84 (m, 1H),3.35 (br s, 2H), 3.58 (br s, 2H), 6.82 (d, 1H), 7.01 (d, 1H), 7.12-7.28(m, 4H), 7.58-7.62 (m, 3H), 7.70 (t, 1H), 8.02 (d, 1H), 8.28 (d, 1H),8.35 (d, 1H), 8.80 (br s, 1H), 9.18 (d, 1H); HPLC Purity: 97.00%; LCMS:533 (M⁺+1).

N-(2-fluoro-4-(4-(3-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-48)

¹H NMR (400 MHz, CDCl₃) δ: 1.77 (pentate, 2H), 2.20-2.42 (m, 6H), 2.62(t, 2H), 3.40 (br s, 2H), 3.60 (br s, 2H), 6.90 (d, 1H), 7.01 (d, 1H),7.12-7.30 (m, 4H), 7.58-7.62 (m, 2H), 7.70 (t, 1H), 8.02 (d, 1H), 8.28(d, 1H), 8.37 (d, 1H), 8.81 (br s, 1H), 9.18 (d, 1H); HPLC Purity:98.00%; LCMS: 533 (M⁺+1).

N-(2-methyl-4-(4-((3-(trifluoromethyl)pyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-49)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.14 (br s,2H), 3.46 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.51 (t, 1H), 7.62-7.77(m, 2H), 8.17 (d, 1H), 8.25 (dd, 2H), 8.58 (d, 1H), 8.78 (s, 1H), 9.18(s, 1H), 9.39 (s, 1H); HPLC Purity: 97.97%; LCMS: 592 (M⁺+23).

N-(2-methyl-4-(4-((4-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-50)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.46 (br s,4H), 3.64 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.62-7.77 (m, 3H),8.20-8.30 (m, 2H), 8.56 (d, 1H), 8.78 (s, 1H), 8.90 (s, 1H), 9.18 (s,1H), 9.39 (br s, 1H); HPLC Purity: 98.71%; LCMS: 570 (M⁺+1).

N-(4-(4-((5-chloropyridin-3-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-51)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.26 (br s,4H), 3.51 (s, 2H), 6.98 (s, 2H), 7.06 (s, 1H), 7.62-7.77 (m, 2H), 7.81(s, 1H), 8.25 (dd, 2H), 8.41 (s, 1H), 8.50 (s, 1H), 8.58 (d, 1H), 9.11(s, 1H), 9.39 (s, 1H); HPLC Purity: 99.11%; LCMS: 536 (M⁺).

N-(4-(4-((3-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-52)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.21 (br s,2H), 3.46 (br s, 2H), 3.64 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H),7.37-7.41 (m, 1H), 7.62-7.77 (m, 3H), 8.22 (d, 1H), 8.27 (d, 1H), 8.36(s, 1H), 8.58 (d, 1H), 9.10 (s, 1H), 9.38 (s, 1H); HPLC Purity: 99.15%;LCMS: 520 (M⁺+1).

N-(4-(4-(cyclohexylmethyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-53)

¹H NMR (400 MHz, DMSO-d6) δ:0.72-0.90 (m, 2H), 1.05-1.21 (m, 4H), 1.41(br s, 1H), 1.56-1.74 (m, 4H), 2.01 (s, 3H), 2.25 (br s, 5H), 3.20 (brs, 2H), 3.46 (br s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.62-7.77 (m, 2H),8.25 (dd, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 9.39 (br s, 1H); HPLC Purity:94.98%; LCMS: 507 (M⁺+1).

N-(2-methyl-4-(4-(pyridin-3-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-54)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.30 (br s, 4H), 3.41 (br s,4H), 3.46 (s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.31 (t, 1H), 7.62-7.77(m, 2H), 8.25 (dd, 2H), 8.42 (s, 2H), 8.58 (d, 1H), 9.18 (s, 1H), 9.39(s, 1H); HPLC Purity: 96.73%; LCMS: 502 (M⁺+1).

N-(2-methyl-4-(4-((1-phenylcyclopropyl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-55)

¹H NMR (400 MHz, DMSO-d6) δ: 0.65 (s, 2H), 0.78 (s, 2H), 2.01 (s, 3H),2.36 (br s, 4H), 2.63 (br s, 2H), 3.41 (br s, 4H), 6.97 (s, 2H), 7.06(s, 1H), 7.12 (t, 1H), 7.20-7.28 (m, 4H), 7.62-7.77 (m, 2H), 8.25 (dd,2H), 8.58 (d, 1H), 9.18 (s, 1H), 9.39 (s, 1H); HPLC Purity: 96.19%;LCMS: 541 (M⁺+1).

N-(2-fluoro-4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-56)

¹H NMR (400 MHz, DMSO-d6) δ: 2.45 (s, 4H), 3.56 (br s, 4H), 3.66 (s,2H), 7.06-7.26 (m, 4H), 7.28-7.39 (m, 2H), 7.62-7.79 (m, 3H), 8.21-8.36(m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.85 (s, 1H); HPLC Purity: 93.25%;LCMS: 522.57 (M⁺).

N-(4-(4-(3-chlorobenzyl)piperazine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-57)

¹H NMR (400 MHz, DMSO-d6) δ: 2.25 (s, 4H), 3.41 (br s, 4H), 3.47 (s,2H), 7.01-7.09 (m, 2H), 7.22-7.36 (m, 5H), 7.61-7.78 (m, 2H), 8.21-8.38(m, 2H), 8.55-8.60 (m, 1H), 9.01 (s, 1H), 9.9 (s, 1H) HPLC Purity:97.30%; LCMS: 539 (M⁺).

N-(4-(4-(2,4-dichlorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-58)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20-2.39 (m, 4H), 3.41 (br s, 4H), 3.46(s, 2H), 3.56 (s, 3H), 6.61-6.81 (m, 3H), 7.36-7.60 (m, 3H), 7.62-7.67(m, 2H), 8.25 (d, 1H), 8.41-8.58 (m, 2H), 9.18 (s, 1H), 10.25 (s, 1H);HPLC Purity: 98.16%; LCMS: 585.50 (M⁺).

N-(4-(4-(3,5-dichlorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-59)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20-2.39 (m, 4H), 3.26 (br s, 4H), 3.46(s, 2H), 3.56 (s, 3H) 6.61-6.85 (m, 3H), 7.26 (s, 2H), 7.45 (s, 1H),7.63-7.78 (m, 2H), 8.20-8.60 (m, 3H), 9.18 (s, 1H), 10.25 (s, 1H); HPLCPurity: 97.92%; LCMS: 584.1 (M⁺).

N-(4-(4-(3-chloro-4-fluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-60)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20-2.39 (m, 4H), 3.26 (br s, 4H), 3.46(s, 2H), 3.56 (s, 3H), 6.61-6.85 (m, 3H), 7.21-7.55 (m, 3H), 7.62-7.75(m, 2H), 8.21-8.60 (m, 3H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity:98.4%; LCMS: 569 (M⁺).

N-(3-methoxy-4-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-61)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20-2.39 (m, 4H), 2.97 (br s, 4H), 3.46(s, 2H), 3.56 (s, 3H), 6.61-6.85 (m, 3H), 7.42-7.58 (m, 2H), 7.61-7.78(m, 4H), 8.21-8.60 (m, 3H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity:99.24%; LCMS: 584.6 (M⁺).

N-(4-(4-(3,4-dichlorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-62)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 2.97 (br s, 4H), 3.46(s, 2H), 3.56 (s, 3H), 6.61-6.85 (m, 3H), 7.25 (d, 1H), 7.45-7.60 (m,2H), 7.63-7.80 (m, 2H), 7.62-7.77 (m, 3H), 8.21-8.60 (m, 3H), 9.18 (s,1H), 10.25 (s, 1H), HPLC Purity: 98.45%; LCMS: 585.50 (M⁺).

N-(4-(4-(2-fluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-63)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 2.97 (br s, 4H), 3.46(s, 2H), 3.56 (s, 3H), 6.61-6.85 (m, 3H), 7.06-7.45 (m, 4H), 7.71 (s,2H), 8.21-8.60 (m, 3H), 9.18 (s, 1H), 10.25 (s, 1H) HPLC Purity: 98.29%;LCMS: 534.8 (M⁺).

N-(4-(4-(2,4-difluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-64)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 2.97 (br s, 4H), 3.46(s, 2H), 3.56 (s, 3H), 6.61-6.85 (m, 3H), 7.01-7.21 (m, 2H), 7.35-7.42(m, 1H), 7.62-7.78 (m, 2H), 8.21-8.60 (m, 3H), 9.18 (s, 1H), 10.25 (s,1H) HPLC Purity: 99.00%; LCMS: 552.59 (M⁺).

N-(4-(4-(2,3-dichlorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-65)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 3.21 (br s, 4H), 3.46(s, 2H), 3.61 (s, 3H), 6.61-6.85 (m, 3H), 7.35-7.59 (m, 3H), 7.63-7.75(m, 2H), 8.21-8.60 (m, 3H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity:99.17%; LCMS: 585.50 (M⁺).

N-(4-(4-(4-chloro-2-fluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-66)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 3.25 (br s, 4H), 3.46(s, 2H), 3.61 (s, 3H), 6.61-6.85 (m, 3H), 7.22-7.42 (m, 3H), 7.65-7.75(m, 2H), 8.21-8.60 (m, 3H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity:91.3%; LCMS: 569 (M⁺).

N-(4-(4-(2,3-difluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-67)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 3.21 (br s, 4H), 3.46(s, 2H), 3.61 (s, 3H), 6.61-6.85 (m, 3H), 7.12-7.40 (m, 3H), 7.65-7.75(m, 2H), 8.21-8.62 (m, 3H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity:98.39%; LCMS: 552.5 (M⁺).

N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-68)

¹H NMR (400 MHz, DMSO-d6) δ:0.10-0.15 (m, 2H), 0.70-0.82 (m, 1H),1.20-1.30 (m, 2H), 2.02-2.42 (m, 6H), 2.90-3.05 (m, 4H), 3.63 (s, 3H),6.61-6.85 (m, 3H), 7.65-7.75 (m, 2H), 8.21-8.60 (m, 3H), 9.18 (s, 1H),10.25 (s, 1H), HPLC Purity: 98%; LCMS: 480.5 (M⁺).

N-(4-(4-((5-chloropyridin-3-yl)methyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-69)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 3.21 (br s, 4H), 3.46(s, 2H), 3.61 (s, 3H), 6.61-6.85 (m, 3H), 7.62-7.83 (m, 3H), 8.21-8.60(m, 5H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity: 96.1%; LCMS: 551(M⁺).

N-(4-(4-((3-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-70)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 3.21 (br s, 4H), 3.46(s, 2H), 3.61 (s, 3H), 6.61-6.85 (m, 3H), 7.38-4.42 (m, 1H), 7.61-7.78(m, 3H), 8.21-8.60 (m, 4H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity:99.54%; LCMS: 535.5 (M⁺).

N-(3-methoxy-4-(4-((4-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-71)

¹H NMR (400 MHz, DMSO-d6) δ: 2.08-2.39 (m, 4H), 3.15 (br s, 4H), 3.46(s, 2H), 3.61 (s, 3H), 6.61-6.85 (m, 3H), 7.62-7.77 (m, 3H), 8.21-8.60(m, 3H), 8.70-8.90 (m, 2H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity:98.48%; LCMS: 585.6 (M⁺).

N-(3-methoxy-4-(4-((3-(trifluoromethyl)pyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-72)

¹H NMR (400 MHz, DMSO-d6) δ: 2.25 (br s, 4H), 2.85 (br s, 2H), 3.42 (brs, 2H), 3.58 (s, 3H), 3.76 (br s, 2H), 6.60 (d, 1H), 6.78 (s, 1H), 6.92(d, 1H), 7.46 (t, 1H), 7.63-7.70 (m, 2H), 8.18 (d, 1H), 8.22 (d, 1H),8.37-8.45 (dd, 2H), 8.78 (d, 1H), 9.18 (s, 1H), 10.29 (s, 1H); HPLCPurity: 95.85%; LCMS: 586.1 (M⁺+1).

N-(4-(4-((3-methoxypyridin-2-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-73)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.39 (br s, 4H), 3.46 (s,4H), 3.61 (s, 2H), 3.79 (s, 3H), 6.97 (s, 2H), 7.06 (s, 1H), 7.22-7.32(s, 1H), 7.39 (d, 1H), 7.64-7.81 (m, 2H), 8.12 (d, 1H), 8.21-8.36 (m,2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.39 (s, 1H); HPLC Purity: 99.29%;LCMS: 532 (M⁺).

N-(4-(4-((4-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-74)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.46 (br s,6H), 3.79 (s, 3H), 6.97-7.06 (m, 3H), 7.10 (s, 1H), 7.66-7.79 (m, 2H),8.21-8.38 (m, 4H), 8.57 (d, 1H), 9.16 (s, 1H), 9.39 (s, 1H); HPLCPurity: 98.22%; LCMS: 532 (M⁺+1).

N-(4-(4-((5-fluoropyridin-3-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-75)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.25 (s,4H), 3.58 (s, 2H), 6.96 (s, 2H), 7.06 (s, 1H), 7.60-7.79 (m, 3H),8.21-8.30 (m, 3H), 8.43 (s, 1H), 8.57 (d, 1H), 9.16 (s, 1H), 9.39 (s,1H); HPLC Purity: 94.48%; LCMS: 520.3 (M⁺+1).

N-(4-(4-((5-fluoropyridin-3-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-76)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.25 (s,4H), 3.58 (s, 2H), 6.96 (s, 2H), 7.06 (s, 1H), 7.42 (t, 1H), 7.60-7.79(m, 2H), 8.21-8.30 (m, 3H), 8.46 (s, 1H), 8.57 (d, 1H), 9.16 (s, 1H),9.39 (s, 1H); HPLC Purity: 99.87%; LCMS: 520.3 (M⁺+1).

N-(4-(4-(2-fluoro-4-methoxybenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-77)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.25 (br s,4H), 3.58 (s, 2H), 3.76 (s, 3H), 6.65-6.78 (m, 2H), 6.96 (s, 2H), 7.06(s, 1H), 7.21 (t, 1H), 7.61-7.79 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d,1H), 9.16 (s, 1H), 9.39 (s, 1H); HPLC Purity: 99.37%; LCMS: 549.3(M++1).

N-(4-(4-((3-chloropyridin-4-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-78)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.24 (br s,4H), 3.59 (br s, 2H), 6.97 (s, 2H), 7.06 (s, 1H), 7.46 (d, 1H),7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.44 (d, 1H), 8.52-8.60 (m, 2H),9.16 (s, 1H), 9.39 (s, 1H); HPLC Purity: 99.46%; LCMS: 536 (M⁺).

N-(4-(4-(3-fluoro-4-methoxybenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-79)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.25 (s,4H), 3.58 (s, 2H), 3.79 (s, 3H), 6.96-7.18 (m, 6H), 7.60-7.78 (m, 2H),8.21-8.36 (m, 2H), 8.57 (d, 1H), 9.16 (s, 1H), 9.39 (s, 1H); HPLCPurity: 99.01%; LCMS: 549.3 (M⁺+1).

N-(4-(4-(2,4-difluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-80)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.31 (s, 6H), 3.56 (s,3H), 6.75 (s, 1H), 6.81 (d, 1H), 7.05 (t, 1H), 7.20 (t, 1H), 7.37-7.42(m, 2H), 7.66-7.79 (m, 2H), 8.25 (d, 2H), 8.57 (d, 1H), 9.13 (s, 1H),9.21 (s, 1H); HPLC Purity: 99.51%; LCMS: 553 (M′).

N-(4-(4-(2,3-difluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-81)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.31 (br s, 6H), 3.58 (s,3H), 6.75 (s, 1H), 6.81 (d, 1H), 7.05-7.12 (m, 1H), 7.22-7.38 (m, 1H),7.41 (d, 1H), 7.66-7.79 (m, 2H), 8.25 (d, 2H), 8.57 (d, 1H), 9.13 (s,1H), 9.21 (s, 1H); HPLC Purity: 96.99%; LCMS: 553 (M′).

N-(4-(4-(4-chloro-2-fluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-82)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.31 (s, 6H), 3.58 (s,3H), 6.75 (s, 1H), 6.81 (d, 1H), 7.21 (d, 1H), 7.33-7.44 (m, 3H),7.66-7.79 (m, 2H), 8.25 (d, 2H), 8.57 (d, 1H), 9.13 (s, 1H), 9.21 (s,1H); HPLC Purity: 97.45%; LCMS: 553 (M′).

N-(4-(4-(3,4-dichlorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-83)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.31 (br s, 6H), 3.55 (s,3H), 6.75 (s, 1H), 6.81 (d, 1H), 7.23 (d, 1H), 7.42 (d, 1H), 7.55-7.61(m, 2H), 7.66-7.79 (m, 2H), 8.25 (d, 2H), 8.57 (d, 1H), 9.13 (s, 1H),9.21 (s, 1H); HPLC Purity: 99.49%; LCMS: 585 (M⁺).

N-(4-(4-(3,5-dichlorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-84)

¹H NMR (400 MHz, DMSO-d6) δ 2.37 (br s, 4H), 3.31 (br s, 6H), 3.55 (s,3H), 6.75 (s, 1H), 6.81 (d, 1H), 7.38 (s, 1H), 7.42-7.50 (m, 3H),7.66-7.79 (m, 2H), 8.25 (d, 2H), 8.59 (d, 1H), 9.13 (s, 1H), 9.21 (s,1H); HPLC Purity: 99.43%; LCMS: 585 (M⁺).

N-(4-(4-(2,4-dichlorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-85)

¹H NMR (400 MHz, DMSO-d6) δ 2.37 (br s, 4H), 3.31 (br s, 4H), 3.41 (s,2H), 3.57 (s, 3H), 6.75 (s, 1H), 6.81 (d, 1H), 7.38-7.59 (m, 4H),7.64-7.79 (m, 2H), 8.25 (d, 2H), 8.59 (d, 1H), 9.13 (s, 1H), 9.21 (s,1H); HPLC Purity: 99.87%; LCMS: 585 (M⁺).

N-(2-methoxy-4-(4-(2-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-86)

¹H NMR (400 MHz, DMSO-d6) δ:1.18 (d, 3H), 2.37 (br s, 4H), 2.41 (m, 1H),2.46 (br s, 4H), 3.36 (br s, 2H), 3.41 (s, 3H), 6.75 (s, 1H), 6.81 (d,1H), 7.16-7.36 (m, 5H), 7.41 (d, 1H), 7.62-7.77 (m, 2H), 8.24 (d, 2H),8.57 (d, 1H), 9.18 (s, 1H), 9.39 (s, 1H); HPLC Purity: 99.41%; LCMS: 545(M⁺).

N-(2-methoxy-4-(4-(3-phenylpropyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-87)

¹H NMR (400 MHz, DMSO-d6) δ:1.65 (t, 2H), 2.27-2.38 (m, 6H), 2.52-2.58(m, 2H), 3.36 (br s, 6H), 3.41 (br s, 5H), 6.75 (s, 1H), 6.81 (d, 1H),7.16-7.32 (m, 5H), 7.41 (d, 1H), 7.62-7.77 (m, 2H), 8.24 (d, 2H), 8.57(d, 1H), 9.18 (s, 1H), 9.39 (s, 1H); HPLC Purity: 99.69%; LCMS: 545(M⁺).

N-(2-methoxy-4-(4-phenethylpiperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-88)

¹H NMR (400 MHz, DMSO-d6) δ: 2.39 (s, 4H), 2.61-2.72 (m, 2H), 3.36 (brs, 6H), 3.41 (s, 3H), 6.75 (s, 1H), 6.81 (d, 1H), 7.16-7.32 (m, 5H),7.41 (d, 1H), 7.62-7.77 (m, 2H), 8.24 (d, 2H), 8.57 (d, 1H), 9.18 (s,1H), 9.39 (s, 1H); HPLC Purity: 99.41%; LCMS: 545 (M⁺+1).

N-(4-(4-((5-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-89)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.39 (br s, 4H), 3.31 (br s,4H), 3.61 (s, 2H), 6.98-7.08 (m, 3H), 7.44-7.56 (m, 2H), 7.62-7.79 (m,3H), 8.21-8.32 (m, 2H), 8.41 (s, 1H), 8.56-8.60 (m, 1H), 9.16 (s, 1H),9.38 (s, 1H); HPLC Purity: 99.82%; LCMS: 520 (M⁺+1).

N-(4-(4-(2,4-dimethoxybenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-90)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.31 (br s,4H), 3.42 (s, 2H), 3.76 (s, 6H), 6.42 (d, 1H), 6.52 (s, 1H), 6.97-7.18(m, 4H), 7.64-7.79 (m, 2H), 8.21-8.36 (m, 2H), 8.59 (d, 1H), 9.16 (s,1H), 9.39 (s, 1H); HPLC Purity: 94.33%; LCMS: 561 (M⁺+1).

N-(4-(4-(2-fluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-91)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.42 (s,2H), 3.56 (s, 3H), 6.79 (s, 1H), 6.82 (d, 1H), 7.15-7.19 (m, 4H),7.21-7.44 (m, 3H), 8.24 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.39 (s,1H); HPLC Purity: 97.44%; LCMS: 535 (M⁺).

N-(4-(4-(3-chloro-4-fluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-92)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.42 (s,2H), 3.56 (s, 3H), 6.79 (s, 1H), 6.82 (d, 1H), 7.21-7.45 (m, 4H),7.62-7.78 (m, 2H), 8.24 (d, 2H), 8.57 (d, 1H), 9.16 (s, 1H), 9.19 (s,1H); HPLC Purity: 99.19%; LCMS: 569 (M⁺).

N-(4-(4-(2,3-dichlorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-93)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.42 (s,2H), 3.59 (s, 3H), 6.79 (s, 1H), 6.82 (d, 1H), 7.24-7.58 (m, 4H),7.62-7.78 (m, 2H), 8.24 (d, 2H), 8.57 (d, 1H), 9.16 (s, 1H), 9.19 (s,1H); HPLC Purity: 99.80%; LCMS: 585 (M⁺).

N-(2-methoxy-4-(4-(pyridin-3-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-94)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.32 (s, 4H), 3.42 (s,3H), 3.56 (s, 2H), 6.79 (s, 1H), 6.82 (d, 1H), 7.30-7.46 (m, 2H),7.62-7.79 (m, 3H), 8.24 (d, 2H), 8.40-8.59 (m, 2H), 9.10 (s, 1H), 9.19(s, 1H); HPLC Purity: 98.45%; LCMS: 518 (M⁺+1).

N-(4-(4-(3-chlorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-95)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.42 (s,3H), 3.59 (s, 2H), 6.79 (s, 1H), 6.82 (d, 1H), 7.21-7.44 (m, 5H),7.62-7.78 (m, 2H), 8.24 (d, 2H), 8.57 (d, 1H), 9.16 (s, 1H), 9.19 (s,1H); HPLC Purity: 98.92%; LCMS: 551 (M⁺).

N-(4-(4-(cyclopentylmethyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-96)

¹H NMR (400 MHz, DMSO-d6) δ: 1.15-1.19 (m, 2H), 1.40-1.71 (m, 6H),2.01-2.05 (m, 1H), 2.30-2.37 (br s, 6H), 3.36 (s, 4H), 3.42 (s, 3H),6.79 (s, 1H), 6.82 (d, 1H), 7.41 (d, 1H), 7.62-7.78 (m, 2H), 8.24 (d,2H), 8.57 (d, 1H), 9.12 (s, 1H), 9.19 (s, 1H); HPLC Purity: 99.58%;LCMS: 509 (M⁺+1).

N-(4-(4-(2,4-dimethoxybenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-97)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (br s, 6H), 3.42 (s,3H), 3.78 (s, 6H), 6.42-6.51 (m, 2H), 6.79 (s, 1H), 6.82 (d, 1H), 7.41(d, 1H), 7.62-7.78 (m, 2H), 8.24 (d, 2H), 8.57 (d, 1H), 9.12 (s, 1H),9.19 (s, 1H); HPLC Purity: 96.10%; LCMS: 577 (M⁺+1).

N-(4-(4-(3,5-difluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-98)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.52 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 6.97-7.16 (m, 3H), 7.41(d, 1H), 7.62-7.80 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.08 (s,1H), 9.18 (s, 1H); HPLC Purity: 99.30%; LCMS: 553 (M⁺+1).

N-(2-methoxy-4-(4-((4-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-99)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.62 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 6.97-7.16 (m, 3H), 7.41(d, 1H), 7.64-7.80 (m, 3H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 8.76 (d,1H), 8.84 (s, 1H), 9.08 (s, 1H), 9.18 (s, 1H); HPLC Purity: 96.90%;LCMS: 586 (M⁺+1).

N-(4-(4-((5-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-100)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.59 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 7.41-7.52 (m, 2H),7.64-7.80 (m, 3H), 8.21-8.30 (m, 2H), 8.41 (s, 2H), 8.57 (d, 2H), 9.08(s, 1H), 9.18 (s, 1H); HPLC Purity: 98.81%; LCMS: 536 (M⁺+1).

N-(2-methoxy-4-(4-((3-methoxypyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-101)

¹H NMR (400 MHz, DMSO-d6) δ: 2.39 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.59 (s, 2H), 3.79 (s, 3H), 6.78 (s, 1H), 6.81 (d, 1H), 7.21-7.43(m, 3H), 7.64-7.80 (m, 2H), 8.05 (s, 1H), 8.24-8.30 (m, 2H), 8.57 (d,1H), 9.08 (s, 1H), 9.18 (s, 1H); HPLC Purity: 99.08%; LCMS: 548 (M⁺+1).

N-(2-methoxy-4-(4-((4-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-102)

¹H NMR (400 MHz, DMSO-d6) δ: 2.39 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.55 (s, 2H), 3.81 (s, 3H), 6.78 (s, 1H), 6.81 (d, 1H), 7.01 (s,1H), 7.41 (s, 1H), 7.64-7.80 (m, 2H), 8.24-8.39 (m, 4H), 8.59 (d, 1H),9.08 (s, 1H), 9.18 (s, 1H); HPLC Purity: 97.31%; LCMS: 548 (M⁺+1).

N-(4-(4-(cyclopentylmethyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-103)

¹H NMR (400 MHz, DMSO-d6) δ: 0.81-0.84 (m, 1H), 1.1-1.32 (m, 3H),1.4-1.75 (m, 5H), 2.1 (s, 3H), 2.12-2.4 (br s, 6H), 3.18-3.62 (br s,4H), 6.9-7.14 (s, 3H), 7.62-7.77 (m, 2H), 8.21-8.35 (m, 2H), 8.57 (d,1H), 9.18 (s, 1H), 9.39 (s, 1H); HPLC Purity: 99.55%; LCMS: 493.3(M⁺+1).

N-(4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-104)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.2-2.37 (br s, 4H),3.18-3.34 (br s, 2H), 3.42-3.59 (br s, 4H), 6.96 (s, 2H), 7.06-7.16 (m,3H), 7.31 (t, 2H), 7.61-7.79 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H),9.16 (s, 1H), 9.39 (s, 1H); HPLC Purity: 99.31%; LCMS: 519.3 (M⁺+1).

N-(4-(4-(4-methoxybenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-105)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.18-3.28(br s, 4H), 3.46 (s, 2H), 3.71 (s, 3H), 6.82 (d, 2H), 6.96 (d, 2H), 7.06(s, 1H), 7.19 (d, 2H), 7.62-7.77 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d,1H), 9.18 (s, 1H), 9.39 (s, 1H); HPLC Purity: 94.41%. LCMS: 531.15(M⁺+1).

N-(2-methyl-4-(4-((6-methylpyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-106)

¹H NMR (400 MHz, DMSO-d6) δ:2.01 (s, 3H), 2.34 (br s, 4H), 2.39 (s, 3H),3.21 (br s, 4H), 3.58 (s, 2H), 6.97-7.16 (m, 4H), 7.21 (d, 2H),7.62-7.77 (m, 3H), 8.21-8.34 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H); HPLCPurity: 95.18%; LCMS: 516.35 (M⁺+1).

N-(2-methyl-4-(4-((tetrahydrofuran-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-107)

¹H NMR (400 MHz, DMSO-d6) δ: 0.82-0.84 (m, 1H), 1.22 (s, 2H), 1.42-1.58(br s, 1H), 1.82-1.96 (m, 1H), 2.04 (s, 3H), 2.21-2.31 (m, 5H),3.16-3.51 (br s, 5H), 3.72-3.85 (m, 2H), 6.97-7.04 (m, 3H), 7.62-7.77(m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.18 (s, 1H), 9.39 (s, 1H);HPLC Purity: 98.714%; LCMS: 495.35 (M⁺+1).

N-(4-(4-(cyclopropylmethyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-108)

¹H NMR (400 MHz, DMSO-d6) δ: 0.21 (s, 2H), 0.41 (s, 2H), 0.91 (br s,1H), 2.12 (s, 2H), 2.39 (br s, 4H), 3.36 (s, 4H), 3.41 (s, 3H), 6.78 (s,1H). 6.81 (d, 1H), 7.41 (d, 1H), 7.62-7.82 (m, 2H), 8.21-8.30 (m, 2H),8.57 (d, 1H), 9.08 (s, 1H), 9.19 (s, 1H); HPLC Purity: 99.74%; LCMS: 481(M⁺+1).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-109)

¹H NMR (400 MHz, DMSO-d6) δ: 2.31 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.44 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 7.21-7.43 (m, 5H),7.62-7.78 (m, 2H), 8.21-8.30 (m, 2H), 8.55 (d, 1H), 9.08 (s, 1H), 9.19(s, 1H); HPLC Purity: 94.85%; LCMS: 551 (M⁺).

N-(2-methoxy-4-(4-(4-(trifluoromethyl)benzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-110)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.59 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 7.41-7.56 (m, 3H),7.62-7.78 (m, 4H), 8.21-8.30 (m, 2H), 8.58 (d, 1H), 9.08 (s, 1H), 9.19(s, 1H); HPLC Purity: 98.62%; LCMS: 585 (M⁺+1).

N-(2-methoxy-4-(4-(4-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-111)

¹H NMR (400 MHz, DMSO-d6) δ: 2.35 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.43 (s, 2H), 3.66 (s, 3H), 6.76-6.90 (m, 4H), 7.19 (d, 2H), 7.41(s, 1H), 7.62-7.78 (m, 2H), 8.21-8.30 (m, 2H), 8.58 (d, 1H), 9.05 (s,1H), 9.19 (s, 1H); HPLC Purity: 97.73%; LCMS: 547 (M⁺+1).

N-(4-(4-((5-chloropyridin-3-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-112)

¹H NMR (400 MHz, DMSO-d6) δ: 2.31 (br s, 4H), 3.37 (s, 4H), 3.41 (s,3H), 3.55 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 7.41 (d, 1H), 7.62-7.82(m, 3H), 8.21-8.30 (m, 2H), 8.41-8.61 (m, 3H), 9.05 (s, 1H), 9.19 (s,1H); HPLC Purity: 99.46%; LCMS: 553 (M⁺+1).

N-(4-(4-((3-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-113)

¹H NMR (400 MHz, DMSO-d6) δ 2.39 (br s, 4H), 3.37 (s, 4H), 3.41 (s, 3H),3.61 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 7.41-7.45 (m, 2H), 7.62-7.80(m, 4H), 8.21-8.39 (m, 3H), 8.59 (s, 1H), 9.18 (s, 1H); HPLC Purity:96.15%; LCMS: 536 (M⁺).

N-(2-methoxy-4-(4-((3-(trifluoromethyl)pyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-114)

¹H NMR (400 MHz, DMSO-d6) δ: 2.39 (br s, 4H), 3.37 (s, 4H), 3.43 (s,3H), 3.70 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 7.41-7.59 (m, 2H),7.64-7.80 (m, 2H), 8.18 (d, 1H), 8.24-8.29 (m, 2H), 8.59 (d, 1H), 8.79(d, 1H), 9.08 (s, 1H), 9.18 (s, 1H); HPLC Purity: 99.41%; LCMS: 586(M++1).

N-(4-(4-((3-fluoropyridin-4-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-115)

¹H NMR (400 MHz, DMSO-d6) δ: 2.45 (s, 4H), 3.47 (s, 4H), 3.56 (s, 3H),3.61 (s, 2H), 6.72-6.85 (m, 2H), 7.38-7.42 (m, 2H), 7.62-7.81 (m, 2H),8.21-8.40 (m, 3H), 8.57 (d, 2H), 9.08 (s, 1H), 9.21 (s, 1H); HPLCPurity: 99.2%; LCMS: 535 (M⁺).

N-(4-(4-((5-fluoropyridin-3-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-116)

¹H NMR (400 MHz, DMSO-d6) δ: 2.45 (s, 4H), 3.47 (s, 4H), 3.56 (s, 3H),3.61 (s, 2H), 6.72-6.85 (m, 2H), 7.42 (d, 1H), 7.58-7.81 (m, 3H),8.21-8.40 (m, 3H), 8.57 (d, 2H), 9.08 (s, 1H), 9.21 (s, 1H); HPLCPurity: 99.8%; LCMS: 535 (M⁺).

N-(4-(4-(cyclohexylmethyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-117)

¹H NMR (400 MHz, DMSO-d6) δ:0.70-0.84 (m, 2H), 1.01-1.21 (m, 3H),1.35-1.42 (m, 1H), 1.61-1.74 (m, 5H), 2.02 (d, 2H), 2.25 (br s, 4H),3.47 (s, 2H), 3.56 (s, 3H), 3.61 (s, 2H), 6.65-6.82 (m, 2H), 7.42 (d,1H), 7.65-7.80 (m, 2H), 8.35 (d, 2H), 8.60 (d, 1H), 9.08 (s, 1H), 9.19(d, 1H); HPLC Purity: 99.7%; LCMS: 522 (M⁺).

N-(4-(4-((2-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-118)

¹H NMR (400 MHz, DMSO-d6) δ: 2.01 (s, 3H), 2.37 (br s, 4H), 3.46 (s,4H), 3.56 (s, 2H), 3.86 (s, 3H), 6.96-7.02 (m, 3H), 7.61-7.79 (m, 3H),8.0 (d, 1H), 8.22-8.35 (m, 2H), 8.58 (d, 1H), 9.15 (s, 1H), 9.35 (s,1H); HPLC Purity: 97.2%; LCMS: 531 (M⁺).

N-(3-methoxy-4-(4-(pyridin-3-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-119)

¹H NMR (400 MHz, DMSO-d6) δ:2.01-2.38 (s, 4H), 2.97 (br s, 2H), 3.46 (s,4H), 3.56 (s, 3H), 6.65-6.97 (m, 3H), 7.36 (m, 1H), 7.61-7.78 (m, 3H),8.20-8.58 (m, 5H), 9.18 (s, 1H), 10.25 (s, 1H); HPLC Purity: 99.09%;LCMS: 517.6 (M⁺).

N-(4-(4-(3,5-difluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-120)

¹H NMR (400 MHz, DMSO-d6) δ: 2.31 (br s, 4H), 3.02 (br s, 2H), 3.46 (brs, 4H), 3.59 (s, 3H), 6.81 (d, 1H), 6.78 (s, 1H), 6.85 (d, 1H),7.06-7.18 (m, 3H), 7.71-7.76 (m, 2H), 8.24 (d, 1H), 8.42-8.58 (m, 2H),9.18 (s, 1H), 10.28 (s, 1H); HPLC Purity: 99.20%; LCMS: 553 (M⁺+1).

N-(4-(4-(4-chlorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-121)

¹H NMR (400 MHz, DMSO-d6) δ: 2.36 (br s, 4H), 3.37 (s, 4H), 3.42 (s,3H), 3.46 (s, 2H), 6.78 (s, 1H), 6.81 (d, 1H), 7.24-7.43 (m, 5H),7.62-7.78 (m, 2H), 8.21-8.30 (m, 2H), 8.57 (d, 1H), 9.08 (s, 1H), 9.19(s, 1H); HPLC Purity: 95.65%; LCMS: 551 (M⁺).

N-(4-(4-((5-fluoropyridin-3-yl)methyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-122)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (s, 2H), 2.25 (br s, 2H), 2.95 (br s,2H), 3.52 (d, 5H), 6.61 (d, 1H), 6.78 (s, 1H), 6.83 (d, 1H), 7.60 (d,1H), 7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.34 (s, 1H), 8.39-8.48 (m, 3H),9.16 (d, 1H), 10.30 (s, 1H); HPLC Purity: 99.58%; LCMS: 536 (M⁺+1).

N-(4-(4-((3-fluoropyridin-4-yl)methyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-123)

¹H NMR (400 MHz, DMSO-d6) δ: 2.21 (br s, 2H), 2.30 (br s, 2H), 3.00 (brs, 2H), 3.58 (d, 5H), 6.61 (d, 1H), 6.78 (s, 1H), 6.84 (d, 1H), 7.44 (t,1H), 7.70-7.79 (m, 2H), 8.28 (d, 1H), 8.40 (d, 1H), 8.44 (d, 2H), 8.51(s, 2H), 9.16 (d, 1H), 10.30 (s, 1H); HPLC Purity: 90.34%; LCMS: 536(M⁺+1).

N-(4-(4-((5-fluoropyridin-2-yl)methyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-124)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (br s, 2H), 2.25 (br s, 2H), 2.95 (brs, 2H), 3.41 (br s, 2H), 3.58 (s, 3H), 6.61 (d, 1H), 6.78 (s, 1H), 6.83(d, 1H), 7.47 (t, 1H), 7.60-7.78 (m, 2H), 8.24 (d, 1H), 8.39-8.48 (m,3H), 9.16 (d, 1H), 10.30 (s, 1H); HPLC Purity: 99.57%; LCMS: 536 (M⁺+1).

N-(4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-125)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (br s, 2H), 2.25 (br s, 2H), 2.95 (brs, 2H), 3.42 (s, 2H), 3.52 (s, 3H), 6.60 (d, 1H), 6.78 (s, 1H), 6.82 (d,1H), 7.00-7.16 (m, 3H), 7.30 (q, 1H), 7.64-7.71 (m, 2H), 8.28 (d, 1H),8.34 (s, 1H), 8.38 (d, 1H), 9.16 (d, 1H), 10.30 (s, 1H); HPLC Purity:99.82%; LCMS: 535 (M⁺+1).

N-(4-(4-(3-chlorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-126)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (br s, 2H), 2.25 (br s, 2H), 2.97 (brs, 2H), 3.42 (s, 2H), 3.52 (s, 3H), 6.61 (d, 1H), 6.78 (s, 1H), 6.82 (d,1H), 7.24 (d, 1H), 7.28-7.37 (m, 2H), 8.28 (d, 1H), 8.39 (s, 1H), 8.50(d, 1H), 9.16 (d, 1H), 10.30 (s, 1H); HPLC Purity: 99.53%; LCMS: 551(M⁺).

N-(3-methoxy-4-(4-(4-methoxybenzyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-127)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (br s, 2H), 2.25 (br s, 2H), 2.97 (brs, 2H), 3.31 (br s, 2H), 3.59 (s, 2H), 3.63 (s, 3H), 6.61 (d, 1H), 6.78(s, 1H), 6.82 (d, 3H), 7.12-7.21 (m, 2H), 7.62-7.70 (m, 2H), 8.28 (d,1H), 8.39 (s, 1H), 8.50 (d, 1H), 9.16 (d, 1H), 10.26 (s, 1H); HPLCPurity: 90.80%; LCMS: 546 (M⁺+1).

N-(4-(4-(2,4-dimethoxybenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-128)

¹H NMR (400 MHz, DMSO-d6) δ: 2.25 (br s, 2H), 2.97 (br s, 2H), 3.42 (brs, 4H), 3.59 (s, 2H), 3.63 (s, 3H), 3.73 (s, 6H), 6.45 (d, 1H), 6.50 (s,1H), 6.64 (d, 1H), 6.78 (s, 1H), 6.82 (d, 1H), 7.12 (d, 1H), 7.65-7.72(m, 2H), 8.28 (d, 1H), 8.40 (s, 1H), 8.50 (d, 1H), 9.16 (d, 1H), 10.26(s, 1H); HPLC Purity: 99.78%; LCMS: 577 (M⁺+1).

N-(4-(4-(cyclohexylmethyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-129)

¹H NMR (400 MHz, DMSO-d6) δ: 0.78 (q, 2H), 1.11 (d, 2H), 1.40 (br s,1H), 1.54-1.71 (m, 2H), 1.99-2.30 (m, 8H), 2.90 (br s, 4H), 3.45 (d,1H), 3.59 (s, 3H), 3.70 (s, 1H), 6.61 (d, 1H), 6.76 (s, 1H), 6.82 (d,3H), 7.62-7.70 (m, 2H), 8.28 (d, 1H), 8.40 (s, 1H), 8.47 (m, 1H), 9.10(d, 1H), 10.26 (s, 1H); HPLC Purity: 98.50%; LCMS: 546 (M⁺+1).

N-(3-methoxy-4-(4-((3-methoxypyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-130)

¹H NMR (400 MHz, DMSO-d6) δ:2.22 (br s, 2H), 2.38 (br s, 2H), 2.87 (brs, 4H), 3.41 (s, 3H), 3.59 (br s, 5H), 3.73 (s, 2H), 6.76 (s, 1H), 6.82(d, 1H), 7.21 (s, 1H), 7.40 (d, 1H), 7.62-7.69 (m, 2H), 8.03 (s, 1H),8.27 (d, 1H), 8.39 (s, 1H), 8.50 (m, 1H), 9.10 (d, 1H), 10.23 (s, 1H);HPLC Purity: 99.86%; LCMS: 548 (M⁺+1).

N-(3-methoxy-4-(4-((4-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-131)

¹H NMR (400 MHz, DMSO-d6) δ:2.22 (br s, 2H), 2.38 (br s, 2H), 2.90 (brs, 4H), 3.41 (s, 3H), 3.55 (s, 3H), 3.80 (s, 2H), 6.60 (d, 1H), 6.72 (s,1H), 6.82 (d, 1H), 7.00 (d, 1H), 7.62-7.69 (m, 2H), 8.29 (s, 2H), 8.35(d, 1H), 8.39 (s, 1H), 8.50 (m, 1H), 9.10 (d, 1H); HPLC Purity: 92.10%;LCMS: 548 (M⁺+1).

N-(4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-132)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (br s, 2H), 2.25 (br s, 2H), 2.95 (brs, 4H), 3.42 (s, 2H), 3.52 (s, 3H), 6.60 (d, 1H), 6.78 (s, 1H), 6.82 (d,1H), 7.10 (t, 2H), 7.23 (t, 2H), 7.63-7.71 (m, 2H), 8.25 (d, 1H), 8.40(d, 1H), 8.48 (d, 1H), 9.16 (d, 1H), 10.30 (s, 1H); HPLC Purity: 99.62%;LCMS: 535 (M⁺+1).

N-(4-(4-((3-chloropyridin-4-yl)methyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-133)

¹H NMR (400 MHz, DMSO-d6) δ: 2.24 (br s, 2H), 2.25 (br s, 2H), 2.95 (brs, 4H), 3.58 (s, 5H), 6.61 (d, 1H), 6.74 (s, 1H), 6.83 (d, 1H), 7.47 (d,1H), 7.63-7.72 (m, 2H), 8.23 (d, 1H), 8.39-8.49 (m, 3H), 8.54 (s, 1H),9.16 (d, 1H), 10.30 (s, 1H); HPLC Purity: 98.63%; LCMS: 552 (M⁺).

N-(3-methoxy-4-(4-((tetrahydrofuran-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-134)

¹H NMR (400 MHz, DMSO-d6) δ:1.42 (m, 2H), 1.83 (m, 2H), 2.19 (d, 2H),2.24-2.39 (m, 4H), 2.95 (br s, 4H), 3.48 (d, 1H), 3.56 (s, 3H), 3.63 (q,2H), 6.60 (d, 1H), 6.76 (s, 1H), 6.81 (d, 1H), 7.63-7.70 (m, 2H), 8.24(d, 1H), 8.40 (d, 1H), 8.50 (d, 1H), 9.10 (d, 1H), 10.26 (s, 1H); HPLCPurity: 98.40%; LCMS: 511 (M⁺+1).

N-(3-methoxy-4-(4-((2-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-135)

¹H NMR (400 MHz, DMSO-d6) δ:2.22 (br s, 2H), 2.38 (br s, 4H), 2.90 (brs, 4H), 3.41 (s, 3H), 3.55 (s, 3H), 3.80 (s, 2H), 6.61 (d, 1H), 6.75 (s,1H), 6.82 (d, 1H), 6.97 (t, 1H), 7.60-7.73 (m, 3H), 8.02 (s, 1H), 8.27(d, 1H), 8.39 (s, 1H), 8.50 (m, 1H), 9.10 (d, 1H), 10.28 (s, 1H); HPLCPurity: 99.85%; LCMS: 548 (M⁺+1).

N-(3-methoxy-4-(4-((5-(trifluoromethyl)pyridin-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-136)

¹H NMR (400 MHz, DMSO-d6) δ 2.22 (br s, 2H), 2.38 (br s, 2H), 2.99 (brs, 4H), 3.58 (s, 3H), 3.67 (s, 2H), 6.61 (d, 1H), 6.74 (s, 1H), 6.82 (d,1H), 7.62-7.73 (m, 3H), 8.19 (d, 1H), 8.26 (d, 1H), 8.d, 1H), 8.50 (m,1H), 8.82 (s, 1H), 9.10 (d, 1H), 10.30 (s, 1H); HPLC Purity: 94.67%;LCMS: 586 (M⁺+1).

N-(4-(4-(cyclopentylmethyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-137)

¹H NMR (400 MHz, DMSO-d6) δ: 1.10 (sextet, 2H), 1.38-1.50 (m, 3H),1.55-1.61 (m, 3H), 1.99 (pentet, 1H), 2.07 (d, 2H), 2.30 (br s, 4H),2.90 (br s, 4H), 3.59 (s, 3H), 6.60 (d, 1H), 6.72 (s, 1H), 6.82 (d, 1H),7.62-7.69 (m, 2H), 8.25 (s, 1H), 8.40 (d, 1H), 8.47 (d, 1H), 9.10 (d,1H), 10.24 (s, 1H); HPLC Purity: 99.86%; LCMS: 509 (M⁺+1).

N-(4-(4-(2-fluoro-4-methoxybenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-138)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20 (br s, 2H), 2.35 (br s, 2H), 2.90 (brs, 4H), 3.41 (s, 3H), 3.60 (s, 3H), 3.78 (s, 2H), 6.61 (d, 1H),6.70-6.80 (m, 2H), 6.84 (d, 1H), 7.22 (t, 1H), 7.70-7.80 (m, 2H), 8.26(d, 1H), 8.42 (d, 1H), 8.50 (d, 1H), 9.16 (s, 1H), 10.28 (s, 1H); HPLCPurity: 90.48%; LCMS: 565 (M⁺+1).

N-(4-(4-(3-fluoro-4-methoxybenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-139)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20 (br s, 2H), 2.35 (br s, 2H), 2.97 (brs, 4H), 3.42 (s, 3H), 3.59 (s, 3H), 3.82 (s, 2H), 6.61 (d, 1H), 6.80 (s,1H), 6.84 (d, 1H), 7.02-7.18 (m, 3H), 7.70-7.80 (m, 2H), 8.26 (d, 1H),8.42 (d, 1H), 8.50 (d, 1H), 9.16 (s, 1H), 10.28 (s, 1H); HPLC Purity:99.65%; LCMS: 565 (M⁺+1).

N-(4-(4-(4-fluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-140)

¹H NMR (400 MHz, DMSO-d6) δ: 2.24 (br s, 4H), 3.20-3.45 (m, 6H), 3.61(s, 3H), 6.77 (s, 1H), 6.82 (d, 1H), 7.21 (t, 2H), 7.28 (t, 2H), 7.40(d, 1H), 7.65-7.77 (m, 2H), 8.26 (d, 2H), 8.56 (d, 1H), 9.07 (s, 1H),9.20 (s, 1H); HPLC Purity: 95.43%; LCMS: 535 (M⁺+1).

N-(2-methoxy-4-(4-((tetrahydrofuran-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-141)

¹H NMR (400 MHz, DMSO-d6) δ:1.45 (m, 2H), 1.86 (m, 2H), 2.20 (d, 2H),2.24-2.39 (m, 4H), 2.95 (br s, 4H), 3.48 (d, 1H), 3.56 (s, 3H), 3.63 (q,2H), 6.79 (s, 1H), 6.83 (d, 1H), 7.42 (d, 1H), 7.70-7.80 (m, 2H), 8.42(d, 2H), 8.59 (d, 1H), 9.04 (br s, 1H), 9.18 (s, 1H); HPLC Purity:98.88%; LCMS: 511 (M⁺+1).

N-(4-(4-(4-chloro-3-fluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-142)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.42 (s,3H), 3.56 (s, 2H), 6.78 (s, 1H), 6.84 (d, 1H), 7.18 (s, 1H), 7.31-7.56(m, 3H), 7.63-7.81 (m, 2H), 8.24-8.30 (m, 2H), 8.57 (d, 1H), 9.08 (s,1H), 9.19 (d, 1H); HPLC Purity: 97.47%; LCMS: 569 (M⁺).

N-(4-(4-((3-chloropyridin-4-yl)methyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-143)

¹H NMR (400 MHz, DMSO-d6) δ: 2.41 (br s, 4H), 3.36 (s, 4H), 3.44 (s,3H), 3.60 (s, 2H), 6.78 (s, 1H), 6.82 (d, 1H), 7.41-7.51 (m, 2H),7.65-7.80 (m, 2H), 8.22-8.30 (m, 2H), 8.42-8.58 (m, 3H), 9.08 (s, 1H),9.18 (d, 1H); HPLC Purity: 99.17%; LCMS: 552 (M⁺).

N-(4-(4-(3-fluorobenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-144)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.42 (s,3H), 3.56 (s, 2H), 6.78 (s, 1H), 6.84 (d, 1H), 7.18 (s, 1H), 7.31-7.56(m, 3H), 7.63-7.81 (m, 2H), 8.24-8.30 (m, 2H), 8.57 (d, 1H), 9.08 (s,1H), 9.19 (d, 1H); HPLC Purity: 97.47%; LCMS: 535 (M⁺).

N-(2-methoxy-4-(4-((2-methoxypyridin-3-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-145)

¹H NMR (400 MHz, DMSO-d6) δ: 2.37 (br s, 4H), 3.36 (s, 4H), 3.41 (s,3H), 3.46 (s, 2H), 3.81 (s, 3H), 6.78 (s, 1H), 6.81 (d, 1H), 6.97-7.01(m, 1H), 7.41 (d, 1H), 7.62-7.78 (m, 3H), 8.01 (d, 1H), 8.21-8.30 (m,2H), 8.57 (d, 1H), 9.08 (s, 1H), 9.19 (d, 1H); HPLC Purity: 99.95%;LCMS: 548 (M⁺).

N-(2-methoxy-4-(4-(1-phenylethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-146)

¹H NMR (400 MHz, DMSO-d6) δ:1.21 (d, 3H), 2.37 (br s, 4H), 3.36-3.41 (m,8H), 6.71 (s, 1H), 6.78 (d, 1H), 7.11-7.29 (m, 5H), 7.36 (d, 1H),7.60-7.76 (m, 2H), 8.21-8.30 (m, 2H), 8.48 (d, 1H), 9.01 (s, 1H), 9.12(s, 1H); HPLC Purity: 95.62%; LCMS: 531 (M⁺+1).

N-(2-methoxy-4-(4-((1-phenylcyclopropyl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-147)

¹H NMR (400 MHz, DMSO-d6) δ: 0.06 (s, 2H), 0.08 (s, 2H), 2.37 (br s,4H), 3.16 (s, 4H), 3.41 (br s, 5H), 6.78 (s, 1H), 6.81 (s, 1H), 7.12 (s,2H), 7.19-7.26 (m, 4H), 7.42 (d, 1H), 7.65-7.80 (m, 2H), 8.25-8.31 (m,2H), 8.58 (d, 1H), 9.10 (s, 1H), 9.19 (s, 1H); HPLC Purity: 99.97%;LCMS: 557 (M⁺+1).

N-(4-(4-(3-fluoro-4-methoxybenzyl)piperazine-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-148)

¹H NMR (400 MHz, DMSO-d6) δ: 2.31 (br s, 4H), 3.32 (s, 4H), 3.41 (s,2H), 3.43 (s, 3H), 3.80 (s, 3H), 6.78 (s, 1H), 6.82 (d, 1H), 6.98-7.18(m, 3H), 7.21 (d, 1H), 7.31 (s, 2H), 7.64-7.80 (m, 2H), 8.21-8.30 (m,2H), 8.57 (d, 1H), 9.08 (s, 1H), 9.19 (s, 1H); HPLC Purity: 92.22%;LCMS: 565 (M⁺+1).

N-(2-methoxy-4-(4-(pyridin-4-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-149)

¹H NMR (400 MHz, DMSO-d6) δ: 2.32 (br s, 4H), 3.41 (s, 3H), 3.50 (s,4H), 3.62 (s, 2H), 6.75 (s, 1H), 6.82 (d, 1H), 7.28 (d, 2H), 7.41 (d,1H), 7.66-7.80 (d, 2H), 8.30 (s, 2H), 8.50 (d, 2H), 8.59 (d, 1H), 9.18(s, 1H); HPLC Purity: 97.52%; LCMS: 518 (M⁺+1).

N-(2-methoxy-4-(4-((tetrahydrofuran-2-yl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-150)

¹H NMR (400 MHz, DMSO-d6) δ: 1.45 (pentet, 2H), 1.78 (pentet, 2H), 1.90(sextet, 1H), 2.30-2.41 (m, 7H), 3.41 (s, 3H), 3.60 (q, 2H), 3.70 (q,2H), 3.95 (pentet, 1H), 6.78 (s, 1H), 6.82 (d, 1H), 7.42 (d, 1H),7.70-7.81 (m, 2H), 8.30 (d, 1H), 8.60 (d, 1H), 9.10 (s, 1H), 9.20 (s,1H); HPLC Purity: 99.24%; LCMS: 511 (M⁺+1).

N-(4-(4-(4-chloro-3-fluorobenzyl)piperazine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide(XIV-151)

¹H NMR (400 MHz, DMSO-d6) δ: 2.19 (br s, 2H), 2.28 (br s, 2H), 2.97 (brs, 4H), 3.44 (s, 3H), 3.58 (s, 2H), 6.61 (d, 1H), 6.78 (s, 1H), 6.83 (d,1H), 7.15 (1H), 7.30 (d, 1H), 7.49 (d, 1H), 7.70-7.78 (m, 2H), 8.24 (d,1H), 8.42 (d, 1H), 8.50 (d, 1H), 9.10 (s, 1H), 10.30 (s, 1H); HPLCPurity: 98.63%; LCMS: 569 (M⁺).

N-(3-methoxy-4-(4-((1-phenylcyclopropyl)methyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-152)

¹H NMR (400 MHz, DMSO-d6) δ: 0.64 (s, 2H), 0.78 (s, 2H), 2.18 (br s,4H), 2.39 (s, 2H), 2.81 (br s, 4H), 3.41 (s, 3H), 6.61 (d, 1H), 6.78 (s,1H), 6.82 (d, 1H), 7.10 (q, 1H), 7.12 (t, 1H), 7.20-7.28 (m, 4H),7.70-7.80 (m, 2H), 8.23 (d, 1H), 8.41 (d, 1H), 8.50 (d, 1H), 9.13 (s,1H), 10.30 (s, 1H); HPLC Purity: 99.99%; LCMS: 557 (M⁺+1).

N-(3-methoxy-4-(4-(pyridin-2-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-153)

¹H NMR (400 MHz, DMSO-d6) δ: 2.22 (br s, 2H), 2.39 (br s, 2H), 2.98 (brs, 2H), 3.57 (br s, 2H), 3.60 (s, 5H), 6.62 (d, 1H), 6.78 (s, 1H), 6.82(d, 1H), 7.20 (s, 1H), 7.40 (d, 1H), 7.66-7.79 (m, 3H), 8.21-8.30 (m,2H), 8.40-8.50 (m, 2H), 9.16 (s, 1H), 10.30 (s, 1H); HPLC Purity:98.14%; LCMS: 518 (M⁺+1).

N-(3-methoxy-4-(4-(pyridin-4-ylmethyl)piperazine-1-carbonyl)phenyl)quinoline-8-sulfonamide(XIV-154)

¹H NMR (400 MHz, DMSO-d6) δ: 2.20 (br s, 2H), 2.30 (br s, 2H), 2.98 (brs, 4H), 3.50 (s, 3H), 3.58 (s, 2H), 6.62 (d, 1H), 6.78 (s, 1H), 6.82 (d,1H), 7.24 (s, 2H), 7.65-7.73 (m, 2H), 8.21-8.30 (m, 2H), 8.40 (d, 1H),8.43-8.50 (m, 2H), 9.10 (s, 1H), 10.23 (br s, 1H); HPLC Purity: 99.69%;LCMS: 518 (M⁺+1).

N-(4-(4-(4-chloro-3-fluorobenzyl)piperazine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-155)

¹H NMR (400 MHz, DMSO-d6) δ:2.01 (s, 3H), 2.38 (br s, 4H), 3.50 (s, 4H),3.56 (s, 2H), 7.00 (s, 2H), 7.06 (s, 1H), 7.18 (d, 1H), 7.35 (d, 1H),7.52 (t, 1H), 7.70-7.80 (m, 2H), 8.29 (q, 2H), 8.59 (d, 1H), 9.15 (s,1H), 9.38 (s, 1H); HPLC Purity: 99.25%; LCMS: 553 (M⁺).

N-(4-(4-benzyl-1,4-diazepane-1-carbonyl)-2-methoxyphenyl)quinoline-8-sulfonamide(XIV-156)

¹H NMR (400 MHz, DMSO-d6) δ: 2.22 (br s, 2H), 3.01 (br s, 2H), 3.52-3.58(m, 9H), 4.39 (br s, 2H), 6.66 (d, 1H), 6.80 (s, 1H), 7.50 (br s, 4H),7.74-7.79 (m, 2H), 8.30 (d, 1H), 8.47 (d, 2H), 8.59 (d, 1H), 9.18 (d,1H), 10.40 (s, 1H); HPLC Purity: 99.00%; LCMS: 531 (M⁺+1).

N-(4-(4-benzyl-1,4-diazepane-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide(XIV-157)

¹H NMR (400 MHz, CD₃OD) δ: 2.06 (s, 3H), 2.14 (br s, 2H), 2.22 (s, 4H),3.58 (br s, 4H), 4.40 (s, 2H), 7.10 (br s, 1H), 7.22 (d, 2H), 7.50 (s,4H), 7.68-7.77 (m, 2H), 8.21 (d, 1H), 8.38 (d, 1H), 8.51 (d, 1H), 9.18(d, 1H); HPLC Purity: 99.04%; LCMS: 515 (M⁺+1).

N-(4-(4-benzyl-1,4-diazepane-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide(XIV-158)

¹H NMR (400 MHz, CDCl₃) δ: 2.21 (br s, 6H), 3.43 (br s, 4H), 4.21 (s,2H), 6.97 (d, 1H), 7.08 (br s, 1H), 7.42 (t, 4H), 7.63-7.68 (m, 2H),7.79 (t, 1H), 8.09 (d, 1H), 8.28 (d, 1H), 8.38 (d, 1H), 9.18 (d, 1H);HPLC Purity: 96.67%; LCMS: 519 (M⁺+1).

N-(4-(4-benzyl-1,4-diazepane-1-carbonyl)-3-chlorophenyl)quinoline-8-sulfonamide(XIV-159)

¹H NMR (400 MHz, CDCl₃) δ: 2.12 (br s, 1H), 2.50 (br s, 1H), 3.09 (br s,2H), 3.29 (br s, 1H), 3.58 (br s, 2H), 3.67 (br s, 2H), 4.20 (s, 2H),4.41 (br s, 1H), 6.99 (d, 2H), 7.28-7.39 (m, 4H), 7.66 (t, 2H), 8.21 (d,1H), 8.38 (d, 1H), 8.42 (d, 1H), 9.18 (s, 1H); HPLC Purity: 95.33%;LCMS: 535 (M⁺).

Synthesis of Reverse Sulfonamide Benzyl and Alkyl Derivatives

The synthesis of compound 151 was carried out from aniline 131 (0.25mmol) by following the similar procedure as mentioned in Scheme 21 forcompounds of formula (VIII) with respective key steps such as esterhydrolysis, amide bond formation in the presence of PyBop followingreductive amination in the presence of sodium tri-acetoxy borohydride.4-(4-benzylpiperazine-1-carbonyl)-N-(quinolin-8-yl)benzenesulfonamide(151a):

¹H NMR (400 MHz, DMSO-d6) δ: 2.24 (br s, 2H), 2.40 (br s, 2H), 3.10 (brs, 2H), 3.55 (s, 2H), 3.59 (s, 2H), 7.21-7.39 (m, 4H), 7.42 (d, 2H),7.58 (d, 2H), 7.91 (d. 2H), 8.37 (d, 1H), 8.81 (s, 1H), 10.15 (br s,1H); HPLC: 99.26%; LCMS: 487 (M⁺+1).

4-(4-benzyl-1,4-diazepane-1-carbonyl)-N-(quinolin-8-yl)benzenesulfonamide(151b)

¹H NMR (400 MHz, DMSO-d6) δ:1.55 (s, 1H), 1.75 (s, 1H), 2.41 (s, 2H),2.52-2.64 (m, 2H), 3.05 (d, 2H), 3.58-3.62 (m, 4H), 7.19-7.32 (m, 3H),7.36-7.47 (m, 2H), 7.58 (d, 1H), 7.63-7.77 (m, 2H), 7.81-7.89 (m, 2H),8.30 (dd, 1H), 8.78 (dd, 1H), 10.05 (s, 1H); HPLC Purity: 99.89%; LCMS:501 (M-+1).

Having thus described several aspects of several embodiments, it is tobe appreciated various alterations, modifications, and improvements willreadily occur to those skilled in the art. Such alterations,modifications, and improvements are intended to be part of thisdisclosure, and are intended to be within the spirit and scope of theinvention. Accordingly, the foregoing description and drawings are byway of example only.

What is claimed is:
 1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein W, X, Y and Z areeach independently selected from CH or N; D and D¹ are independentlyselected from a bond or NR^(b); A is optionally substituted bicyclicheteroaryl; L is a bond, —C(O)—, —(CR^(c)R^(c))_(m)—, —OC(O)—,—(CR^(c)R^(c))_(m)—OC(O)—, —(CR^(c)R^(c))_(m)C(O)—, —NR^(b)C(S)—, or—NR^(b)C(O)—; R¹ is selected from alkyl, cycloalkyl, aryl, heteroaryl,and heterocyclyl; each of which is substituted with 0-5 occurrences ofR^(d); each R³ is independently selected from halo, haloalkyl, alkyl,hydroxyl and —OR^(a) or two adjacent R³ taken together with the carbonatoms to which they are attached form an optionally substituted cyclyl;each R^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl; each R^(b) is independently selected from hydrogen and alkyl;each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl; eachR^(d) is independently selected from halo, haloalkyl, haloalkoxy, alkyl,alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a), —C(O)OR^(a),—SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) taken together with thecarbon atoms to which they are attached form an optionally substitutedheterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is 0, 1, 2; and g is 0,1 or
 2. 2. The compound of claim 1, wherein h is 1 and g is
 1. 3. Thecompound of claim 2, wherein W, X, Y and Z are CH.
 4. The compound ofclaim 3, wherein D is NR^(b) and D¹ is a bond.
 5. The compound of claim4, wherein R^(b) is H, methyl or ethyl.
 6. The compound of any one ofclaims 1-5, wherein L is a bond, —(CR^(c)R^(c))_(m), —NR^(b)C(O)—,—(CR^(c)R)_(m)C(O)—, —C(O)—, or —O(CO)—.
 7. The compound of claim 6,wherein L is a bond.
 8. The compound of claim 7, wherein R¹ is alkyl,aryl or heteroaryl substituted with 0-5 occurrences of R^(d).
 9. Thecompound of claim 6, wherein L is —(CR^(c)R^(c))_(m).
 10. The compoundof claim 9, wherein R¹ is cycloalkyl, aryl, heteroaryl or heterocyclylsubstituted with 0-5 occurrences of R^(d).
 11. The compound of claim 6,wherein L is —NR^(b)C(O)— and R^(b) is hydrogen.
 12. The compound ofclaim 11, wherein R¹ is aryl substituted with 0-5 occurrences of R^(d).13. The compound of claim 6, wherein L is —(CR^(c)R^(c))_(m)—C(O)—. 14.The compound of claim 13, wherein R¹ is cycloalkyl, aryl or heteroarylsubstituted with 0-5 occurrencs of R^(d).
 15. The compound of claim 6,wherein L is —C(O)—.
 16. The compound of claim 15, wherein R¹ is aryl,alkyl, or heteroaryl substituted with 0-5 occurrencs of R^(d).
 17. Thecompound of claim 6, wherein L is —OC(O)—.
 18. The compound of claim 17,wherein R¹ is alkyl, aryl or heterocyclyl substituted with 0-5occurrences of R^(d).
 19. The compound of claim 6, wherein L is—(CR^(c)R^(c))_(m)OC(O)—.
 20. The compound of claim 19, wherein R¹ isheterocyclyl or cycloalkyl substituted with 0-5 occurrences of R^(d).21. The compound of any one of claims 6-20, wherein n is
 0. 22. Thecompound of any one of claims 6-20, wherein n is 1 and R³ is CH₃,CH₂CH₃, OCH₃, OCH₂CH₃, OH, F, C1, or CF₃.
 23. A pharmaceuticalcomposition comprising a compound formula (I):

or a pharmaceutically acceptable salt thereof, wherein: W, X, Y and Zare each independently selected from CH or N; D and D¹ are independentlyselected from a bond or NR^(b); A is optionally substituted aryl oroptionally substituted heteroaryl; L is a bond, —C(O)—,—(CR^(c)R^(c))_(m)—, —OC(O)—, —(CR^(c)R^(c))_(m)—OC(O)—,—(CR^(c)R^(c))_(m)C(O)—, —NR^(b)C(S)—, or —NR^(b)C(O)— (wherein thepoint of the attachment to R¹ is on the left-hand side); R¹ is selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each ofwhich is substituted with 0-5 occurrences of R^(d); each R³ isindependently selected from halo, haloalkyl, alkyl, hydroxyl and—OR^(a), or two adjacent R³ taken together with the carbon atoms towhich they are attached form an optionally substituted heterocyclyl;each R^(a) is independently selected from alkyl, acyl, hydroxyalkyl andhaloalkyl; each R^(b) is independently selected from hydrogen and alkyl;each R^(c) is independently selected from hydrogen, halo, alkyl, alkoxyand halo alkoxy or two R^(c) taken together with the carbon atoms towhich they are attached form an optionally substituted cycloalkyl; eachR^(d) is independently selected from halo, haloalkyl, haloalkoxy, alkyl,alkynyl, nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a), —C(O)OR^(a),—SR^(a), —NR^(a)R^(b) and —OR^(a), or two R^(d) taken together with thecarbon atoms to which they are attached form an optionally substitutedheterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is 0, 1, 2; and g is 0,1 or
 2. 24. The pharmaceutical composition of claim 23, wherein thecompound is a compound of formula (Id):


25. A pharmaceutical composition comprising a compound of any one ofclaims 1-22.
 26. A pharmaceutical composition comprising a compoundrepresented in FIG. 1 or pharmaceutically acceptable salt thereof.
 27. Amethod of modulating PKM2 activity in a subject in need thereof, themethod comprising administering to said subject a pharmaceuticalcomposition of any one of claims 23-26.
 28. A method of treating acancer associated with PKM2 activity in a subject in need thereof, themethod comprising administering to a subject a pharmaceuticalcomposition of any one of claims 23-27.
 29. A compound of formula (I) ora pharmaceutically acceptable salt thereof:

wherein: W, X, Y and Z are each independently selected from CH or N; Dand D¹ are independently selected from a bond or NR^(b); A is optionallysubstituted bicyclic heteroaryl; L is a bond, —C(O)—,—(CR^(c)R^(c))_(m)—, —OC(O)—, —(CR^(c)R^(c))_(m)—OC(O)—,—(CR^(c)R^(c))_(m)C(O)—, —NR^(b)C(S)—, or —NR^(b)C(O)—; R¹ is selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each ofwhich is substituted with 0-5 occurrences of R^(d); each R³ isindependently selected from halo, haloalkyl, alkyl, hydroxyl and —OR^(a)or two adjacent R³ taken together with the carbon atoms to which theyare attached form an optionally substituted cyclyl; each R^(a) isindependently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;each R^(b) is independently selected from hydrogen and alkyl; each R^(c)is independently selected from hydrogen, halo, alkyl, alkoxy and haloalkoxy or two R^(c) taken together with the carbon atoms to which theyare attached form an optionally substituted cycloalkyl; each R^(d) isindependently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl,nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a), —C(O)OR^(a), —SR^(a),—NR^(a)R^(b) and —OR^(a), or two R^(d) taken together with the carbonatoms to which they are attached form an optionally substitutedheterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is 0, 1, 2; and g is 0,1 or 2; for use as a medicament.
 30. A use of a compound of formula (I)or a pharmaceutically acceptable salt thereof:

wherein: W, X, Y and Z are each independently selected from CH or N; Dand D¹ are independently selected from a bond or NR^(b); A is optionallysubstituted bicyclic heteroaryl; L is a bond, —C(O)—,—(CR^(c)R^(c))_(m)—, —OC(O)—, —(CR^(c)R^(c))_(m)—OC(O)—,—(CR^(c)R^(c))_(m)C(O)—, —NR^(b)C(S)—, or —NR^(b)C(O)—; R¹ is selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl; each ofwhich is substituted with 0-5 occurrences of R^(d); each R³ isindependently selected from halo, haloalkyl, alkyl, hydroxyl and —OR^(a)or two adjacent R³ taken together with the carbon atoms to which theyare attached form an optionally substituted cyclyl; each R^(a) isindependently selected from alkyl, acyl, hydroxyalkyl and haloalkyl;each R^(b) is independently selected from hydrogen and alkyl; each R^(c)is independently selected from hydrogen, halo, alkyl, alkoxy and haloalkoxy or two R^(c) taken together with the carbon atoms to which theyare attached form an optionally substituted cycloalkyl; each R^(d) isindependently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl,nitro, cyano, hydroxyl, —C(O)R^(a), —OC(O)R^(a), —C(O)OR^(a), —SR^(a),—NR^(a)R^(b) and —OR^(a), or two R^(d) taken together with the carbonatoms to which they are attached form an optionally substitutedheterocyclyl; n is 0, 1, or 2; m is 1, 2 or 3; h is 0, 1, 2; and g is 0,1 or 2; in the manufacture of a medicament for modulating PKM2 activityin a subject in need thereof or for treating cancer associated with PKM2activity in a subject in need thereof.